Isoquinolines as inhibitors of hpk1

ABSTRACT

Isoquinoline compounds and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibitng HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to International PatentApplication No. PCT/CN2017/078790 filed 30 Mar. 2017 and InternationalPatent Application No. PCT/CN2018/076908 filed 15 Feb. 2018, thecontents of which applications are hereby incorporated by reference intheir entireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created 30 Mar. 2018, isnamed P34138 US SL.TXT and is 21 KB in size.

FIELD OF THE INVENTION

This invention pertains to compounds that modulate the function of HPK1and are useful for treatment of HPK1 mediated diseases and conditionssuch as cancer.

BACKGROUND

The major treatment modalities used by oncologists to treat cancer aresurgical resection, radiation therapy, and classical chemotherapeuticdrugs. Unfortunately, surgical resection is not a viable option for manytumors or forms of cancers. Further, radiation therapy andchemotherapeutic drugs do not target only diseased cells and therefore,end up damaging healthy cells. Therapeutics that more specificallytarget tumor cells are being developed by taking advantage oftumor-specific expression of antigens or inappropriate overexpression oractivation of specific proteins within tumor cells, but tumor cells areprone to mutation and can become resistant to drugs that specificallytarget tumor cells.

A new cancer treatment paradigm has emerged that harnesses the patient'sown immune system to overcome immunoevasive strategies utilized by manycancers and to enhance anti-tumor immunity. One such strategy is toinhibit negative regulators of immune responses that normally functionto maintain peripheral tolerance, allowing tumor antigens to berecognized as non-self entities.

The hematopoietic progenitor kinase 1 (HPK1) is an example of a negativeregulator of dendritic cell activation, and T and B cell responses thatcan be targeted to enhance anti-tumor immunity. HPK1 is expressedpredominantly by hematopoietic cells, including early progenitors. In Tcells, it is believed that HPK1 negatively regulates T cell activationby reducing the persistence of signaling microclusters byphosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM204:681-691) and Gads at Thr254, which leads to the recruitment of14-3-3 proteins that bind to the phosphorylated SLP76 and Gads,releasing the SLP76-Gads-14-3-3 complex from LAT-containingmicroclusters (Lasserre et al. (2011) J Cell Biol 195(5):839-853). HPK1can also become activated in response to prostaglandin E2, which isoften secreted by tumors, contributing to the escape of tumor cells fromthe immune system.

BRIEF SUMMARY

Antagonists of the enzyme HPK1 are provided herein. The compounds have astructure set forth in Formula I or Ia or are pharmaceuticallyacceptable salts, metabolites, prodrugs, or derivatives thereof. Furtherprovided are methods of preparing the compounds of Formula I or Ia.

The compounds find use in inhibiting HPK1 kinase activity, enhancing animmune response, and in the treatment of HPK1-dependent disorders.Accordingly, pharmaceutical compositions comprising a compound ofFormula I or Ia or a pharmaceutically acceptable salt, prodrug,metabolite, or derivative thereof and a pharmaceutically acceptablecarrier are also provided. Methods of inhibiting HPK1 comprisecontacting HPK1 with an effective amount of a compound of Formula I orIa or a pharmaceutically acceptable salt, prodrug, metabolite, orderivative thereof are provided. Methods of treating a HPK1-dependentdisorder comprise administering to a subject in need thereof a compoundof Formula I or Ia or a pharmaceutical formulation thereof are provided.Also provided is a kit for treating a HPK1-dependent disorder, the kitcomprising a pharmaceutical composition comprising a compound of FormulaI or Ia; and instructions for use.

DETAILED DESCRIPTION

Disclosed herein, are compounds of Formula I or Ia and pharmaceuticalcompositions thereof that are inhibitors or modulators of HPK1(hematopoietic progenitor kinase 1). As such, the compounds andcompositions are useful in treating diseases and disorders mediated byHPK1. An example of a method of treating is in the case of a subject whois suffering from cancer. The compounds can be used not only to combatcancer, but can also advantageously be used to enhance an immuneresponse in a subject in need thereof.

The presently disclosed subject matter will now be described more fullyhereinafter. However, many modifications and other embodiments of thepresently disclosed subject matter set forth herein will come to mind toone skilled in the art to which the presently disclosed subject matterpertains having the benefit of the teachings presented in the foregoingdescriptions. Therefore, it is to be understood that the presentlydisclosed subject matter is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims. Inother words, the subject matter described herein covers allalternatives, modifications, and equivalents. In the event that one ormore of the incorporated literature, patents, and similar materialsdiffers from or contradicts this application, including but not limitedto defined terms, term usage, described techniques, or the like, thisapplication controls. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in this field. All publications,patent applications, patents, and other references mentioned herein areincorporated by reference in their entirety.

Definitions

The term “substituent” refers to an atom or a group of atoms thatreplaces a hydrogen atom on a molecule. The term “substituted” denotesthat a specified molecule bears one or more substituents. The term “acompound of the formula” or “a compound of formula” or “compounds of theformula” or “compounds of formula” refers to any compound selected fromthe genus of compounds as defined by Formula I or Ia.

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 12 carbon atoms. The term“lower alkyl” refers to a C₁-C₆ alkyl chain. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.Alkyl groups may be optionally substituted with one or moresubstituents.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈), preferably(C₂₋₆), with at least one site of unsaturation, i.e., a carbon-carbon,sp² double bond, wherein the alkenyl radical may be optionallysubstituted independently with one or more substituents describedherein, and includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. Examples include, but are notlimited to, ethylenyl or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and thelike.

The term “alkenylene” refers to linear or branched-chain divalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈), preferably(C₂₋₆), with at least one site of unsaturation, i.e., a carbon-carbon,sp² double bond, wherein the alkenylene radical may be optionallysubstituted substituted independently with one or more substituentsdescribed herein, and includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. Examplesinclude, but are not limited to, ethylenylene or vinylene (—CH═CH—),allyl (—CH₂CH═CH—), and the like.

The term “alkoxy” refers to an —O-alkyl group. Alkoxy groups may beoptionally substituted with one or more substituents.

The term “haloalkyl” refers to an alkyl radical that is substituted byone or more halo substituents. Examples of haloalkyl groups includedifluoromethyl (CHF2), trifluoromethyl (CF₃), and 2,2,2-trifluoroethyl.

As used herein, the term “halogen”, “hal” or “halo” means —F, —Cl, —Bror —I.

As used herein, the designations “(CO)” and “C(O)” are used to indicatea carbonyl moiety. Examples of suitable carbonyl moieties include, butare not limited to, ketone and aldehyde moieties.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one saturated ring orhaving at least one non-aromatic ring, wherein the non-aromatic ring mayhave some degree of unsaturation. Cycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a cycloalkyl group may be substituted by asubstituent. Representative examples of cycloalkyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and thelike.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term “heteroaryl” refers to an aromatic 5-10 membered mono- orbi-cyclic where the heteroatoms selected from O, N, or S, and theremainder ring atoms being carbon (with appropriate hydrogen atomsunless otherwise indicated). Heteroaryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heteroaryl group may be substituted by asubstituent. Examples of heteroaryl groups include pyridyl, furanyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl,isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and thelike.

The term “heterocycloalkyl” or “heterocyclyl” refers to a nonaromatic3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 memberedtricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, S, B, P or Si, wherein the nonaromaticring system is completely saturated. Heterocycloalkyl groups may beoptionally substituted with one or more substituents. In one embodiment,0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may besubstituted by a substituent. Representative heterocycloalkyl groupsinclude piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, 1,3-dioxolanyl, tetrahydrofuranyl, tetrahydrothienyl,thienyl, and the like.

The term “hydroxyalkyl” refers to an alkyl substituent which is furthersubstituted with one or more hydroxyl groups. The alkyl portion may befurther optionally substituted with one or more substituents.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in correct valences. Unless otherwise indicatedby context, a hyphen (−) designates the point of attachment of thependant group or radical.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not minor images of oneanother.

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate.”

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

With respect to the nomenclature of a chiral center, the terms “d” and“l” (or plus and minus) configuration are as defined by the IUPACRecommendations.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result, for example, from the oxidation, hydroxylation,reduction, hydrolysis, amidation, deamidation, esterification,deesterification, enzymatic cleavage, and the like, of the administeredcompound. Accordingly, the invention includes metabolites of compoundsof the invention, including compounds produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible, chemically and/or toxicologically, with theother ingredients comprising a formulation and/or the subject beingtreated therewithours.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g.,sodium and potassium) salts, alkaline earth metal (e.g., magnesium)salts, and ammonium salts. A pharmaceutically acceptable salt mayinvolve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt, the salt can havemultiple counter ions. Hence, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counter ion.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers that are nontoxic to the cell or mammal beingexposed thereto at the dosages and concentrations employed. Often thephysiologically acceptable carrier is an aqueous pH buffered solution.Non-limiting examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. In certainembodiments, the pharmaceutically acceptable carrier is a non-naturallyoccurring pharmaceutically acceptable carrier.

Use of the word “inhibitor” herein is meant to mean a molecule thatinhibits activity of HPK1. By “inhibit” herein is meant to decrease theactivity of the target enzyme, as compared to the activity of thatenzyme in the absence of the inhibitor. In some embodiments, the term“inhibit” means a decrease in HPK1 activity of at least about 5%, atleast about 10%, at least about 20%, at least about 25%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, or at least about 95%. In other embodiments, inhibitmeans a decrease in HPK1 activity of about 5% to about 25%, about 25% toabout 50%, about 50% to about 75%, or about 75% to 100%. In someembodiments, inhibit means a decrease in HPK1 activity of about 95% to100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%.Such decreases can be measured using a variety of techniques that wouldbe recognizable by one of skill in the art, including in vitro kinaseassays.

As used herein, a “HPK1 antagonist” or a “HPK1 inhibitor” is a moleculethat reduces, inhibits, or otherwise diminishes one or more of thebiological activities of HPK1 (e.g., serine/threonine kinase activity,recruitment to the TCR complex upon TCR activation, interaction with aprotein binding partner, such as SLP76). Antagonism using the HPK1antagonist does not necessarily indicate a total elimination of the HPK1activity. Instead, the activity could decrease by a statisticallysignificant amount including, for example, a decrease of at least about5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 95% or 100% of the activity of HPK1 compared to anappropriate control. In some embodiments, the HPK1 antagonist reduces,inhibits, or otherwise diminishes the serine/threonine kinase activityof HPK1. In some of these embodiments, the HPK1 antagonist reduces,inhibits, or otherwise diminishes the HPK1-mediated phosphorylation ofSLP76 and/or Gads. The presently disclosed compounds bind directly toHPK1 and inhibit its kinase activity.

By “specific antagonist” is intended an agent that reduces, inhibits, orotherwise diminishes the activity of a defined target greater than thatof an unrelated target. For example, a HPK1 specific antagonist reducesat least one biological activity of HPK1 by an amount that isstatistically greater than the inhibitory effect of the antagonist onany other protein (e.g., other serine/threonine kinases). In someembodiments, the IC₅₀ of the antagonist for the target is about 90%,80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% orless of the IC₅₀ of the antagonist for a non-target. The presentlydisclosed compounds may or may not be a specific HPK1 antagonist. Aspecific HPK1 antagonist reduces the biological activity of HPK1 by anamount that is statistically greater than the inhibitory effect of theantagonist on any other protein (e.g., other serine/threonine kinases).In certain embodiments, the HPK1 antagonist specifically inhibits theserine/threonine kinase activity of HPK1. In some of these embodiments,the IC₅₀ of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC₅₀ of theHPK1 antagonist for another serine/threonine kinase or other type ofkinase (e.g., tyrosine kinase).

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The term “administration” or “administering” includes routes ofintroducing the compound(s) to a subject to perform their intendedfunction. Examples of routes of administration which can be used includeinjection (subcutaneous, intravenous, parenterally, intraperitoneally,intrathecal), topical, oral, inhalation, rectal and transdermal.

The term “effective amount” includes an amount effective, at dosages andfor periods of time necessary, to achieve the desired result. Aneffective amount of compound may vary according to factors such as thedisease state, age, and weight of the subject, and the ability of thecompound to elicit a desired response in the subject. Dosage regimensmay be adjusted to provide the optimum therapeutic response. Aneffective amount can also be one in which any toxic or detrimentaleffects (e.g., side effects) of the inhibitor compound are notoutweighed by the therapeutically beneficial effects.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound(s), drug or other material,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The term “subject” refers to animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In certain embodiments, thesubject is a human.

The terms “abnormal cell growth,” “unregulated cell growth,” and“hyperproliferative disorder” are used interchangeably in thisapplication. “Abnormal cell growth”, as used herein, unless otherwiseindicated, refers to cell growth that is independent of normalregulatory mechanisms (e.g., loss of contact inhibition).

The term “cancer” refers to the condition in a subject that ischaracterized by unregulated cell growth, wherein the cancerous cellsare capable of local invasion and/or metastasis to noncontiguous sites.As used herein, “cancer cells,” “cancerous cells,” or “tumor cells”refer to the cells that are characterized by this unregulated cellgrowth and invasive property. The term “cancer” encompasses all types ofcancers, including, but not limited to, all forms of carcinomas,melanomas, blastomas, sarcomas, lymphomas and leukemias, includingwithout limitation, bladder cancer, bladder carcinoma, brain tumors,breast cancer, cervical cancer, colorectal cancer, esophageal cancer,endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lungcancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostatecancer, renal carcinoma and thyroid cancer, acute lymphocytic leukemia,acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma,medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoidcancer, and nephroblastoma (Wilm's tumor).

A “chemotherapeutic agent” is a chemical compound or biologic useful inthe treatment of cancer. Examples of chemotherapeutic agents includealkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®);alkyl sulfonates such as busulfan, improsulfan, and piposulfan;aziridines such as benzodopa, carboquone, meturedopa, and uredopa;ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol(dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; a camptothecin (including the synthetic analogue topotecan(HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin,scopolectin, and 9-aminocamptothecin); bryostatin; pemetrexed;callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesinsynthetic analogues); podophyllotoxin; podophyllinic acid; teniposide;cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogues, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; TLK-286; CDP323, an oral alpha-4integrin inhibitor; a sarcodictyin; spongistatin; nitrogen mustards suchas chlorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such asthe enediyne antibiotics (e. g., calicheamicin, especially calicheamicingamma1I and calicheamicin omegaI1 (see, e.g., Nicolaou et al., Angew.Chem Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, includingdynemicin A; an esperamicin; as well as neocarzinostatin chromophore andrelated chromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including ADRIAMYCIN®, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HClliposome injection (DOXIL®) and deoxydoxorubicin), epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C,mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin,puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such asmethotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine(XELODA®), an epothilone, and 5-fluorouracil (5-FU); folic acidanalogues such as denopterin, methotrexate, pteropterin, trimetrexate;purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine,thioguanine; pyrimidine analogs such as ancitabine, azacitidine,6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,enocitabine, and floxuridine; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such asmaytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS NaturalProducts, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium;tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verracurin A, roridin A andanguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); thiotepa; taxoids, e.g., paclitaxel (TAXOL®),albumin-engineered nanoparticle formulation of paclitaxel (ABRAXANE™),and doxetaxel (TAXOTERE®); chloranbucil; 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine (VELBAN®); platinum; etoposide (VP-16); ifosfamide;mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovin;vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin;aminopterin; ibandronate; topoisomerase inhibitor RFS 2000;difluorometlhylornithine (DMFO); retinoids such as retinoic acid;pharmaceutically acceptable salts, acids or derivatives of any of theabove; as well as combinations of two or more of the above such as CHOP,an abbreviation for a combined therapy of cyclophosphamide, doxorubicin,vincristine, and prednisolone, and FOLFOX, an abbreviation for atreatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU andleucovovin.

Additional examples of chemotherapeutic agents include anti-hormonalagents that act to regulate, reduce, block, or inhibit the effects ofhormones that can promote the growth of cancer, and are often in theform of systemic, or whole-body treatment. They may be hormonesthemselves. Examples include anti-estrogens and selective estrogenreceptor modulators (SERMs), including, for example, tamoxifen(including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andtoremifene (FARESTON®); anti-progesterones; estrogen receptordown-regulators (ERDs); estrogen receptor antagonists such asfulvestrant (FASLODEX®); agents that function to suppress or shut downthe ovaries, for example, leutinizing hormone-releasing hormone (LHRH)agonists such as leuprolide acetate (LUPRON® and ELIGARD®), goserelinacetate, buserelin acetate and tripterelin; anti-androgens such asflutamide, nilutamide and bicalutamide; and aromatase inhibitors thatinhibit the enzyme aromatase, which regulates estrogen production in theadrenal glands, such as, for example, 4(5)-imidazoles,aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®),formestanie, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), andanastrozole (ARIMIDEX®). In addition, such definition ofchemotherapeutic agents includes bisphosphonates such as clodronate (forexample, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095,zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®),pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®);as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog);anti-sense oligonucleotides, particularly those that inhibit expressionof genes in signaling pathways implicated in abherant cellproliferation, such as, for example, PKC-alpha, Raf, H-Ras, andepidermal growth factor receptor (EGF-R); vaccines such as THERATOPE®vaccine and gene therapy vaccines, for example, ALLOVECTIN® vaccine,LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitor (e.g.,LURTOTECAN®); an anti-estrogen such as fulvestrant; EGFR inhibitor suchas erlotinib or cetuximab; an anti-VEGF inhibitor such as bevacizumab;arinotecan; rmRH (e.g., ABARELIX®); 17AAG (geldanamycin derivative thatis a heat shock protein (Hsp) 90 poison), and pharmaceuticallyacceptable salts, acids or derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER₂ expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptablesalts, acids and derivatives of any of the above.

In some embodiments, the chemotherapeutic agent is an immunotherapeuticagent. As used herein, an “immunotherapeutic agent” is a compound thatenhances the immune system to help fight cancer, specifically ornon-specifically. Immunotherapeutics include monoclonal antibodies andnon-specific immunotherapies that boost the immune system, such ascytokines, interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-21),interferons (e.g., IFN-α, IFN-β, IFN-γ), GM-CSF, thalidomide,(THALOMID®, Celgene), lenalidomide (REVLIMID®, Celgene), pomalidomide(POMALYST®, Celgene), imiquimod (ZYCLARA®, Valeant). Non-limitingexamples of monoclonal antibodies that are useful as a chemotherapeuticagent include trastuzumab (HERCEPTIN®, Genentech), bevacizumab(AVASTIN®, Genentech), cetuximab (ERBITUX®, Bristol-Myers Squibb),panitumumab (VECTIBIX®, Amgen), ipilimumab (YERVOY®, Bristol-MyersSquibb), rituximab (RITUXAN®, Genentech), alemtuzumab (CAMPATH®,Genzyme), ofatumumab (ARZERRA®, Genmab), gemtuzumab ozogamicin(MYLOTARG®, Wyeth), brentuximab vedotin (ADCETRIS®, Seattle Genetics),⁹⁰Y-labelled ibritumomab tiuxetan (ZEVALIN®, Biogen Idec), ¹³¹I-labelledtositumomab (BEXXAR®, GlaxoSmithKline), ado-trastuzumab emtansine(KADCYLA®, Genentech) blinatumomab (BLINCYTO®, Amgen), pertuzumab(PERJETA®, Genentech), obinutuzumab (GAZYVA®, Genentech), nivolumab(OPDIVO®,) Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck),pidilizumab (CureTech), MPDL3280A (described in WO2010/077634, hereinincorporated by reference in its entirety), MDX-1105 (described inWO2007/005874, herein incorporated by reference in its entirety), andMEDI4736 (described in WO2011/066389 and US2013/034559, each of which isherein incorporated by reference in its entirety). Another usefulimmunotherapeutic agent is AMP-224 (described in WO2010/027827 andWO2011/066342, each of which is incorporated herein in its entirety).

Compounds

The compounds disclosed herein are compounds of Formula I or Ia, orsalts (e.g., pharmaceutically acceptable salts), solvates (e.g.,hydrates), prodrugs, metabolites, or derivatives thereof. Thesecompounds are useful inhibitors of HPK1.

In one aspect, provided is a compound of Formula I:

or salt (e.g., a pharmaceutically acceptable salt), solvate (e.g.,hydrate), prodrug, metabolites or derivative thereof, wherein:

R₁ is hydrogen, halogen, cyano, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆ alkoxyl, optionallysubstituted amino or optionally substituted acylamino;

R₂ is (a), (b), (c), (d), (e), (f), (g) or (h):

-   -   (a) a 5-10 membered heteroaryl or 5-10 membered heterocyclyl,        having 1-4 heteroatoms selected from O, S, and N; and optionally        substituted with one, two, three, four or five substituents; or    -   (b) a C₆₋₁₀ aryl optionally substituted with one, two, three,        four or five substituents; or    -   (c) hydrogen, halogen, cyano, —NR^(b)C(O)R^(a), —NR^(b)SO₂R^(a),        —SO₂NR^(a)R^(b); or —SO₂R^(a); wherein each R^(a) is        independently C₁₋₆ alkyl, and R^(b) is independently hydrogen or        C₁₋₆ alkyl; or R^(a) and R^(b) are taken together with the        atom(s) to which they are attached to form an optionally        substituted 5-10 membered heterocyclyl; or    -   (d) —OR^(a1) or —(C₁₋₆ alkylene)-OR^(a1); wherein each R^(a1) is        independently C₁₋₆ alkyl optionally substituted with C₆₋₁₀ aryl;        5-10 membered heteroaryl; or 5-10 membered heterocyclyl; wherein        the C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered        heterocyclyl are optionally substituted; or    -   (e) a C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionally        substituted with one to five substituents; or    -   (f) a C₃₋₈ cycloalkyl optionally substituted with one to five        substituents;    -   (g) —C(O)NR^(a2)R^(b2) or —NR^(a2)(CO)R^(b2), wherein each        R^(a2) is independently hydrogen or C₁₋₆ alkyl, and R^(b2) is        hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl or        5-10 membered heterocyclyl; or R^(a2) and R^(b2) are taken        together with the atom(s) to which they are attached to form an        optionally substituted 5-10 membered heterocyclyl; wherein the        C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 5-10        membered heterocyclyl are optionally substituted; or    -   (h) 5-10 membered heteroaryl fused with a ring selected from the        group consisting of 5 or 6 membered heteroaryl, 5-10 membered        heterocyclyl, C₆₋₁₀ aryl and C₃₋₇ cycloalkyl, wherein the 5-10        membered heteroaryl of R₂ and the fused ring are optionally        substituted with one to four substituents;

R₃ is hydrogen, cyano, halogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₉ heterocyclyl, or optionally substituted C₁₋₆alkoxy; and

R₄ is A-C(O)— or D;

A is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, C₂₋₉ heterocyclyl,—NHR^(g) or —OR^(h); wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 7 C₂₋₉heteroaryl and C₂₋₉ heterocyclyl of A are optionally substitutedindependently with one, two, three, four or five substituents;

R^(g) and R^(h) are independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, C₆-lo aryl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl; whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉heteroaryl and C₂₋₉ heterocyclyl of R^(g) and R^(h) are optionallysubstituted independently with one, two, three, four or fivesubstituents; and

D is hydrogen, a C₆₋₁₀ aryl, or a 5-10 membered heteroaryl having 1-4heteroatoms selected from O, S, and N; or a 5-10 membered heteroarylfused with a ring selected from the group consisting of 5- or 6-memberedheteroaryl, 5-10 membered heterocyclyl, C₆ aryl and C₃₋₈ cycloalkyl;wherein the 5-10 membered heteroaryl of D and the fused ring areoptionally substituted with one, two, three, four or five substituents.

In one aspect of the general structure of Formula (I):

R₁ is hydrogen, halogen, cyano, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆ alkoxyl, optionallysubstituted amino or optionally substituted acylamino;

R₂ is (a), (b), (c), (d), (e), (f), (g) or (h):

-   -   (a) a 5-10 membered heteroaryl or 5-10 membered heterocyclyl,        having 1-4 heteroatoms selected from O, S, and N; and optionally        substituted with one, two, three, four or five substituents; or    -   (b) a C₆₋₁₀ aryl optionally substituted with one, two, three,        four or five substituents; or    -   (c) hydrogen, —NHSO₂R^(a), —SO₂NR^(a)R^(b); or —SO₂NH₂; wherein        each R^(a) is independently C₁₋₆ alkyl, and R^(b) is hydrogen or        C₁₋₆ alkyl; or    -   (d) —OR^(a1) or —(C₁₋₆ alkylene)-OR^(a1); wherein each R^(a1) is        independently C₁₋₆ alkyl optionally substituted with C₆₋₁₀ aryl;        5-10 membered heteroaryl; or 5-10 membered heterocyclyl; wherein        the 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are        optionally substituted; or    -   (e) a C₁₋₆ alkyl optionally substituted with one to five        substituents; or    -   (f) a C₃₋₈ cycloalkyl optionally substituted with one to five        substituents;    -   (g) —C(O)NR^(a2)R^(b2), wherein each R^(a2) is independently        hydrogen or C₁₋₆ alkyl, and R^(b2) is hydrogen, C₁₋₆ alkyl, 5-10        membered heteroaryl or 5-10 membered heterocyclyl, wherein the        5-10 membered heteroaryl and 5-10 membered heterocyclyl are        optionally substituted; or    -   (h) 5-10 membered heteroaryl fused with a ring selected from the        group consisting of 5 or 6 membered heteroaryl, 5-10 membered        heterocyclyl, C₆ aryl and C₃₋₇ cycloalkyl, wherein the 5-10        membered heteroaryl of R₂ and the fused ring are optionally        substituted with one to four substituents;

R₃ is hydrogen, cyano, halogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₉ heterocyclyl, or optionally substituted C₁₋₆alkoxy; and

R₄ is A-C(O)— or D;

A is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, C₂₋₉ heterocyclyl,—NHR^(g) or —OR^(h); wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₉heteroaryl and C₂₋₉ heterocyclyl of A are optionally substitutedindependently with one, two, three, four or five substituents;

R^(g) and R^(h) are independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, C₆₋₁₀ aryl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl; whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉heteroaryl and C₂₋₉ heterocyclyl of R^(g) and R^(h) are optionallysubstituted independently with one, two, three, four or fivesubstituents; and

D is hydrogen, or a 5-10 membered heteroaryl, having 1-4 heteroatomsselected from O, S, and N; or a 5-10 membered heteroaryl fused with aring selected from the group consisting of 5- or 6-membered heteroaryl,5-10 membered heterocyclyl, C₆ aryl and C₃₋₈ cycloalkyl; wherein the5-10 membered heteroaryl of D and the fused ring are optionallysubstituted with one, two, three, four or five substituents.

In one aspect of the general structure of Formula (I):

-   R₁ is hydrogen, halogen, methyl, CF₃, CHF₂, CH₂OH, or cyano;-   R₂ is:    -   a 5-10 member heteroaryl or 5-10 member heterocyclyl, having 1-4        heteroatoms selected from O, S, and N; and optionally        substituted with one, two, three or four substituents, R₆, R₇,        R₈ and R_(8′), each of which is independently selected from the        group consisting of:        -   i. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆            alkenylene, wherein said alkyl, alkenyl and alkenylene can            be optionally substituted with one to four hydroxyl,            halogen, nitrile, amino, mono(C₁₋₆)alkylamino-,            di(C₁₋₆)alkylamino-, —SO₂R^(y), SONR^(y), —(CO)NR^(y)R^(z)            or —NR^(y)(CO)R^(z), wherein R^(y) and R^(z), in each            instance, is independently hydrogen or C₁₋₆ alkyl, wherein            said alkyl can optionally be substituted with one to four            hydroxyl or halogen;        -   ii. NR^(y)R^(z)—C(O)—, wherein R^(y) and R^(z) are each            independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can            optionally be substituted with one to four hydroxyl or            halogen;        -   iii. hydroxy(C₁₋₆)alkyl;        -   iv. C₁₋₆ alkoxy, wherein said alkoxy can be optionally            substituted with one to four hydroxyl or halogen;        -   v. C₃₋₉ cycloalkyl, substituted or unsubstituted C₆ aryl,            substituted or unsubstituted 5-member heteroaryl, or C₂₋₉            heterocyclyl;        -   vi. halogen;        -   vii. amino;        -   viii. cyano;        -   ix. —NR^(y)(CO)R^(z), wherein R^(y) and R^(z) are each            independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can            optionally be substituted with one to four hydroxyl or            halogen;        -   x. —SO₂R′, wherein R′ is H or C₁₋₆ alkyl;        -   xi. —SO2NR′R″, wherein R′ and R″ are independently H or C₁₋₆            alkyl; and        -   xii. wherein a carbon embedded in said heterocyclyl taken            together with an oxygen to which it is bound can form a            carbonyl; or-   R₂ is C₆₋₁₀ aryl having one, two, three or four substituents    selected from the group consisting of branched or linear C₁₋₆ alkyl,    C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₃₋₄ cycloalkyl, wherein said alkyl,    alkenyl, alkenylene and cycloalkyl can be substituted with amino,    hydroxyl, nitrile, halogen and amide; cyano, hydroxyl, halogen,    nitrile, amino, mono(C₁₋₆)alkylamino-, di(C₁₋₆)alkylamino-,    —SO₂R^(c), SONR^(d), —(CO)NR^(c)R^(d) or —NR^(c)(CO)R^(d),    -   wherein R^(c) and R^(d) are each independently selected from the        group consisting of hydrogen and C₁₋₆ alkyl, wherein said alkyl        can be optionally substituted with one to four hydroxyl or        halogen; or-   R₂ is hydrogen or —SO₂NH₂;-   R₃ is hydrogen, cyano, or halogen; and-   R₄ is A-C(O)—, wherein, A is:    -   i. C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl,        wherein said cycloalkyl, heteroaryl, or heterocyclyl can be        optionally substituted with one, two, three or four of R₅,        wherein R₅ is selected from the group consisting of hydrogen,        branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene,        wherein said alkyl, alkenyl and alkenylene can be substituted        with amino, C₁₋₆ alkoxy, hydroxyl, nitrile, halogen, —SO₂R^(e)        and amide; halogen, hydroxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, cyano,        cyano(C₁₋₆)alkyl, hydroxyl, C₁₋₆ alkoxy, amino, C₂₋₉ heteroaryl,        —SO₂R^(c), and NR^(e)R^(f)—C(O)—, wherein R^(e) and R^(f) are        independently selected from the group consisting of hydrogen and        branched or linear C₁₋₆ alkyl;    -   or, said cycloalkyl or heterocyclyl together with two of R₅ form        a bicyclic or spiro ring, wherein two of R₅ attached to        different carbons are taken together with the carbon to which        each is attached to form a bicyclic, or two of R₅ attached to        the same carbon are taken together with the carbon to which each        is attached to form a spiro ring; and    -   ii. —NHR^(g), wherein R^(g) is selected from the group        consisting of:        -   a. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆            alkenylene, C₂₋₉ heterocyclyl, and C₃₋₇ cycloalkyl, wherein            said alkyl, alkenyl, alkenylene, heterocyclyl and cycloalkyl            can be optionally substituted with hydroxyl, halogen, —CF₂,            —CF₃, amino, di(C₁₋₆)alkylamino, mono(C₁₋₆)alkylamino,            cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′, —SO₂NR′R″,            —(CO)NR′R″, or —NR′(CO)R″, wherein R′ and R″ are            independently H or C₁₋₆ alkyl; and        -   b. C₂₋₉ heteroaryl or C₆₋₁₀ aryl, wherein said heteroaryl            has 1-4 heteroatoms selected from O, S and N; and wherein            said aryl and heteroaryl can be optionally substituted with            one, two, three or four substituents selected from the group            consisting of branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl,            C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl,            hydroxyl, halogen, —CF2, —CF₃, amino, di(C₁₋₆)alkylamino,            mono(C₁₋₆)alkylamino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,            —SO₂R′, —SO₂NR′R″, —(CO)NR′R″, and —NR′(CO)R″, wherein R′            and R″ are independently H or C₁₋₆ alkyl;-   or, R₄ is D, wherein D is:    -   a 5-10 member heteroaryl, having 1-4 heteroatoms selected from        O, S, and N; and optionally substituted with one, two, three or        four substituents.

In one aspect, provided is a compound of Formula Ia:

or salt (e.g., a pharmaceutically acceptable salt), solvate (e.g.,hydrate), prodrug, metabolites or derivative thereof, wherein:

R₁ is hydrogen, halogen, methyl, CF₃, CHF₂, CH₂OH, or cyano;

R₂ is (a), (b), (c), (d), (e), (f), (g) or (h):

-   -   (a) a 5-10 membered heteroaryl or 5-10 membered heterocyclyl,        having 1-4 heteroatoms selected from O, S, and N; and optionally        substituted with one, two, three or four substituents, R₆, R₇,        R₈ and R_(8′), each of which is independently selected from the        group consisting of:        -   i. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆            alkenylene, wherein said alkyl, alkenyl and alkenylene can            be optionally substituted with one to four substituents            independently selected from the group consisting of            hydroxyl, halogen, nitrile, amino, mono(C₁₋₆alkyl)amino-,            di(C₁₋₆alkyl)amino-, —SO₂R^(y), —S(O)NR^(y),            —(CO)NR^(y)R^(z) and —NR^(y)(CO)R^(z), wherein R^(y) and            R^(z), in each instance, is independently hydrogen or C₁₋₆            alkyl, wherein said alkyl can optionally be substituted with            one to four substituents independently selected from the            group consisting of hydroxyl and halogen;        -   ii. NR^(y)R^(z)—C(O)—, wherein R^(y) and R^(z) are each            independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can            optionally be substituted with one to four substituents            independently selected from the group consisting of hydroxyl            and halogen;        -   iii. hydroxy(C₁₋₆ alkyl);        -   iv. C₁₋₆ alkoxy, wherein said alkoxy can be optionally            substituted with one to four substituents independently            selected from the group consisting of hydroxyl and halogen;        -   v. C₃₋₉ cycloalkyl, substituted or unsubstituted C₆ aryl,            substituted or unsubstituted 5-membered heteroaryl, or C₂₋₉            heterocyclyl;        -   vi. halogen;        -   vii. amino;        -   viii. cyano;        -   ix. —NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are each            independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can            optionally be substituted with one to four substituents            independently selected from the group consisting of hydroxyl            and halogen;        -   x. —SO₂R′, wherein R′ is H or C₁₋₆ alkyl;        -   xi. —SO₂NR′R″, wherein R′ and R″ are independently H or C₁₋₆            alkyl;        -   xii. —NR′C(O)OR″, —NR′SO₂NR″ or —NR′S(O)R″, wherein R′ is            independently H or C₁₋₆ alkyl and R″ is independently C₁₋₆            alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl optionally substituted            with C₁₋₆ alkyl; and        -   xiii. wherein a carbon embedded in said heterocyclyl taken            together with an oxygen to which it is bound can form a            carbonyl; or    -   (b) a C₆₋₁₀ aryl having one, two, three or four substituents        selected from the group consisting of branched or linear C₁₋₆        alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₃₋₄ cycloalkyl, wherein        said alkyl, alkenyl, alkenylene and cycloalkyl can be        substituted with amino, hydroxyl, cyano, halogen, amide,        mono(C₁₋₆ alkyl)amino-, di(C₁₋₆ alkyl)amino-, —SO₂R^(c),        —S(O)NR^(d), —C(O)NR^(c)R^(d) and —NR^(c)C(O)R^(d),    -   wherein R^(c) and R^(d) are each independently selected from the        group consisting of hydrogen and C₁₋₆ alkyl, wherein said alkyl        can be optionally substituted with one to four hydroxyl or        halogen; or    -   (c) hydrogen, —NHSO₂R^(a), —SO₂NR^(a)R^(b); or —SO₂NH₂; wherein        each R^(a) is independently C₁₋₆ alkyl, and R^(b) is hydrogen or        C₁₋₆ alkyl; or    -   (d) —OR^(a1) or —(C₁₋₆ alkyl)-OR^(a1); wherein each R^(a1) is        independently C₁₋₆ alkyl optionally substituted with C₆₋₁₀ aryl;        5-10 membered heteroaryl; or 5-10 membered heterocyclyl; wherein        the 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are        optionally substituted with one to four substituents        independently selected from the group consisting of hydroxyl,        oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or    -   (e) a C₁₋₆ alkyl optionally substituted with one to four        substituents independently selected from the group consisting of        hydroxyl, halogen, cyano, amino, mono(C₁₋₆ alkyl)amino, di(C₁₋₆        alkyl)amino, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, and 5-10 membered heterocyclyl; wherein the C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10        membered heterocyclyl are optionally substituted with one to        four substituents independently selected from the group        consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or    -   (f) C₃₋₈ cycloalkyl optionally substituted with one to four        substituents independently selected from the group consisting of        C₁₋₆ alkyl, hydroxyl, halogen, cyano, amino,        mono(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, 5-10 membered        heteroaryl, and 5-10 membered heterocyclyl; wherein the 5-10        membered heteroaryl, and 5-10 membered heterocyclyl are        optionally substituted with one to four substituents        independently selected from the group consisting of hydroxyl,        oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy;    -   (g) —C(O)NR^(a2)R^(b2), wherein each R^(a2) is independently        hydrogen or C₁₋₆ alkyl, and R^(b2) is hydrogen, C₁₋₆ alkyl, 5-10        membered heteroaryl or 5-10 membered heterocyclyl, wherein the        5-10 membered heteroaryl and 5-10 membered heterocyclyl are        optionally substituted with one to four substituents        independently selected from the group consisting of C₁₋₆ alkyl,        C₃₋₇ cycloalkyl, oxo, hydroxyl, halo and cyano; or    -   (h) 5-10 membered heteroaryl fused with a ring selected from the        group consisting of 5 or 6 membered heteroaryl, 5-10 membered        heterocyclyl, C₆ aryl and C₃₋₇ cycloalkyl, wherein the 5-10        membered heteroaryl of R₂ and the fused ring are optionally        substituted with one to four substituents independently selected        from the group consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆        alkoxy;

R₃ is C₁₋₆ alkyl, hydrogen, cyano, or halogen; and

R₄ is A-C(O)— or D, wherein, A is:

-   -   i. C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl,        wherein said cycloalkyl, heteroaryl, or heterocyclyl can be        optionally substituted with one, two, three or four of R₅,        wherein R₅ is selected from the group consisting of hydrogen,        C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenylene,        halogen, cyano, hydroxyl, C₁₋₆ alkoxy, optionally substituted        C₂₋₉ heteroaryl, —SO₂R^(e), —NR^(e)R^(f), —NR^(e)C(O)R^(f) and        NR^(e)R^(f)—C(O)—; wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkenylene of R₅ can be optionally substituted        with one to four substituents independently selected from the        group consisting of C₁₋₆ alkoxy, hydroxyl, halogen, cyano,        —SO₂R^(e), —NR^(e)R^(f) and —C(O)NR^(e)R^(f), wherein R^(e) and        R^(f) in each occurrence are independently selected from the        group consisting of hydrogen and branched or linear C₁₋₆ alkyl;        -   or, said cycloalkyl or heterocyclyl together with two of R₅            form a bicyclic or spiro ring, wherein two of R₅ attached to            different atoms are taken together with the carbon to which            each is attached to form a bicyclic, or two of R₅ attached            to the same carbon are taken together with the carbon to            which each is attached to form a spiro ring;    -   ii. —NHR^(g) or —OR^(h), wherein R^(g) and R^(h) are        independently selected from the group consisting of:        -   a. branched or linear C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₆            alkenyl, C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, and C₃₋₇            cycloalkyl, wherein said alkyl, alkenyl, alkenylene,            heterocyclyl and cycloalkyl can be optionally substituted            with one to four substituents independently selected from            the group consisting of hydroxyl, halogen, —CHF₂, —CF₃,            amino, di(C₁₋₆ alkyl)amino, mono(C₁₋₆ alkyl)amino, cyano,            C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′, —SO₂NR′R″, —C(O)NR′R″,            and —NR′C(O)R″, wherein R′ and R″ are independently H or            C₁₋₆ alkyl; and        -   b. C₂₋₉ heteroaryl or C₆₋₁₀ aryl, wherein said heteroaryl            has 1-4 heteroatoms selected from O, S and N; and wherein            said aryl and heteroaryl can be optionally substituted with            one, two, three or four substituents selected from the group            consisting of branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl,            C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl,            hydroxyl, halogen, —CHF₂, —CF₃, amino, di(C₁₋₆ alkyl)amino,            mono(C₁₋₆ alkyl)amino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,            —SO₂R′, —SO₂NR′R″, —C(O)NR′R″, and —NR′C(O)R″, wherein R′            and R″ are independently H or C₁₋₆ alkyl; or    -   iii. C₁₋₆ alkyl optionally substituted with one to four        substituents independently selected from the group consisting of        hydroxyl, halogen, cyano, C₁₋₆ alkoxy, amino, mono(C₁₋₆        alkyl)amino, di(C₁₋₆ alkyl)amino, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl,        5-10 membered heteroaryl, and 5-10 membered heterocyclyl;        wherein the C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, and 5-10 membered heterocyclyl are optionally        substituted with one to four substituents independently selected        from the group consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆        alkoxy; and    -   D is hydrogen or a 5-10 membered heteroaryl, having 1-4        heteroatoms selected from 0, S, and N; and optionally        substituted with one, two, three or four substituents        independently selected from the group consisting of hydroxyl,        oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or 5-10 membered heteroaryl        fused with a ring selected from the group consisting of 5 or 6        membered heteroaryl, 5-10 membered heterocyclyl, C₆ aryl and        C₃₋₈ cycloalkyl, wherein the 5-10 membered heteroaryl of D and        the fused ring are optionally substituted with one to four        substituents independently selected from the group consisting of        hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy.

In some embodiments, the compound is Formula I or Ia is other than oneor more compounds selected from the group consisting ofN-(8-amino-3-isoquinolinyl)-N′-ethyl-urea,5-[(8-amino-3-isoquinolinyl)amino]-2-pyrazinecarbonitrile, and5-[(8-amino-3-isoquinolinyl)amino]-3-[(1R)-2-(dimethylamino)-1-methylethoxy]-2-pyrazinecarbonitrile,and salts thereof. In some embodiments of the compound of Formula I orIa, at least one of R₂ and R₃ is other than hydrogen. In someembodiments of the compound of Formula I or Ia, R₂ is other thanhydrogen.

In various embodiments of the compounds of Formula I or Ia, the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl areoptionally substituted with one to five substituents. In someembodiments, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₉ cycloalkyl,C₆₋₁₀ aryl, C₂₋₉ heteroaryl, 5-10 membered heteroaryl, 5-10 memberedheterocyclyl or C₂₋₉ heterocyclyl may be independently optionallysubstituted with one to five R³⁰.

In some embodiments, R³⁰, in each instance, is independently C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₉ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉heteroaryl, C₂₋₉ heterocyclyl, halogen, cyano, oxo, —C(O)NR³¹R³²,—C(O)OR³³, —C(═NR³⁶)R³⁴, —C(═NR³⁶)NR³¹R³², —C(═NOR³⁶)R³⁴, cyano,hydrogen, halogen, —R³¹R³², —NR³⁵C(O)R³⁴, —NR³⁵C(O)NR³′R³²,—NR³⁵C(O)OR³³, —NR³⁵S(O)R³⁶; —NR³⁵SO₂R³⁶, —NR³⁵SO₂NR³¹R³², —OR³³,—OC(O)R³⁴, —OC(O)NR³¹R³², —S(O)R³⁶; —SO₂R³⁶, or —SO₂NR³¹R³²; wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₉ cycloalkyl, C₆₋₁₀ aryl,C₂₋₉ heteroaryl, C₂₋₉ heterocyclyl of R³⁰ are optionally substitutedwith one to four R⁴⁰; or two R³⁰ groups are taken together with theparent moiety to with they are attached to form a ring which isoptionally substituted with one to four R⁴⁰;

each R³¹ and R³² is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₉ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉ heteroaryl or C₂₋₉heterocyclyl, each is independently optionally substituted with one tofour R⁴⁰; or R³¹ and R³² are taken together with the nitrogen atom towhich they are attached to form a C₃₋₇ heterocyclyl optionallysubstituted with one to four R⁴⁰;

each R³³, R³⁴ and R³⁵ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₉ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉ heteroaryl orC₂₋₉ heterocyclyl, each is independently optionally substituted with oneto four R⁴⁰;

R³⁶ is C₁₋₆ alkyl optionally substituted with one to four R⁴⁰.

R⁴⁰ in each instance is independently selected from the group consistingof halogen, cyano, oxo, —NR⁴¹R⁴², —SO₂NR⁴¹R⁴², —C(O)NR⁴¹R⁴², —C(O)OR⁴³,—OR⁴³, —NR⁴³C(O)R⁴⁴, —NR⁴³C(O)OR⁴³, —NR⁴³C(O)NR⁴¹R⁴², NR⁴³SO₂R⁴⁵, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉ heteroaryl, or C₂₋₉heterocyclyl; or two R⁴⁰ groups are taken together with the parentmoiety to with they are attached to form a ring which is optionallysubstituted with one to three substituents selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, hydroxyl and oxo; the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀aryl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl of R⁴⁰ are independentlyoptionally substituted with one to three substituents selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, hydroxyl and oxo.

each R⁴¹ and R⁴² is independently hydrogen or C₁₋₆ alkyl; or R⁴¹ and R⁴²are taken together with the nitrogen atom to which they are attached toform a C₃₋₇ heterocyclyl optionally substituted with one to threesubstituents selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl and oxo;

each R⁴³ and R⁴⁴ are independently hydrogen or C₁₋₆ alkyl; and

R⁴⁵ is C₁₋₆ alkyl.

In some embodiments of the compound of Formula I or Ia, the optionallysubstituted C₂₋₉ heteroaryl of R₅ is optionally substituted with C₁₋₆alkyl optionally substituted with one to four substituents independentlyselected from the group consisting of hydroxyl, halogen, cyano, C₁₋₆alkoxy, amino-(C₁₋₆ alkoxy)- and C₂₋₉ heterocyclyl optionallysubstituted with one to four substituents independently selected fromthe group consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy.

Useful values of R₁ are described above. In an embodiment, R₁ ishydrogen and all other variables are as described in Formula I or Ia. Inan embodiment, R₁ is halogen and all other variables are as described inFormula I or Ia. In an aspect of this embodiment, R₁ is fluoro and allother variables are as described in Formula I or Ia. In an embodiment,R₁ is cyano and all other variables are as described in Formula I or Ia.

Useful values of R₃ are described above. In an embodiment, R₃ ishydrogen and all other variables are as described in Formula I or Ia orare as described in any of the embodiments described herein. In anembodiment, R₃ is halogen and all other variables are as described inFormula I or Ia or are as described in any of the embodiments describedherein. In certain aspects of this embodiment, R₃ is fluoro, chloro, orbromo, and all other variables are as described in Formula I or Ia orare as described in any of the embodiments described herein. In aparticular aspect, R₃ is fluoro, and all other variables are asdescribed in Formula I or Ia or are as described in any of theembodiments described herein.

Useful values of R₄ are described above. In certain aspects, R₄ isA-C(O)—, wherein, A is a C₃₋₆ cycloalkyl, which can be optionallysubstituted with one or two of R₅, and all other variables are asdescribed in Formula I or Ia or are as described in any of theembodiments described herein. In certain aspects, A is a C₃₋₅cycloalkyl, which can be optionally substituted with one or two of R₅,and all other variables are as described in Formula I or Ia or are asdescribed in any of the embodiments described herein. In a particularaspect, A is cyclopropyl, which can be optionally substituted with oneor two of R₅, and all other variables are as described in Formula I orIa or are as described in any of the embodiments described herein.

In embodiments where all other variables are as defined in anyembodiment above, R₂ is -A-C(O)—. In some embodiments, A is optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted C₂₋₉ heteroaryl, optionally substituted C₂₋₉heterocyclyl, —NHR^(g) or —OR^(h).

In some embodiments, A is:

i. C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl, wherein saidcycloalkyl, heteroaryl, or heterocyclyl can be optionally substitutedwith one, two, three or four of R₅, wherein R₅ is selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkenylene, halogen, cyano, hydroxyl, C₁₋₆ alkoxy, optionallysubstituted C₂₋₉ heteroaryl, —SO₂R^(e), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)SO₂R^(f) and NR^(e)R^(f)—C(O)—; wherein the C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenylene of R₅ can be optionallysubstituted with one to four substituents independently selected fromthe group consisting of C₁₋₆ alkoxy, hydroxyl, halogen, cyano,—SO₂R^(e), —NR^(e)R^(f), —NR^(e)C(O)R^(f) and —C(O)NR^(e)R^(f), whereinR^(e) and R^(f) in each occurrence are independently selected from thegroup consisting of hydrogen, branched or linear C₁₋₆ alkyl and C₃₋₇cycloalkyl;

-   -   or, said cycloalkyl or heterocyclyl together with two of R₅ form        a bicyclic or spiro ring, wherein two of R₅ attached to        different atoms are taken together with the carbon to which each        is attached to form a bicyclic, or two of R₅ attached to the        same carbon are taken together with the carbon to which each is        attached to form a spiro ring;

ii. —NHR^(g) or —OR^(h), wherein R^(g) and R^(h) are independentlyselected from the group consisting of:

-   -   a. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene,        C₂₋₉ heterocyclyl, and C₃₋₇ cycloalkyl, wherein said alkyl,        alkenyl, alkenylene, heterocyclyl and cycloalkyl can be        optionally substituted with one to four substituents        independently selected from the group consisting of hydroxyl,        halogen, —CHF₂, —CF₃, amino, di(C₁₋₆ alkyl)amino, mono(C₁₋₆        alkyl)amino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′,        —SO₂NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′C(O)NR″R′″,        —NR′SO₂NR″R′″ or —NR′S(O)R″, wherein R′ and R′″ are        independently H or C₁₋₆ alkyl and R″ is independently C₁₋₆        alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl optionally substituted        with C₁₋₆ alkyl; or R″ and R′″ are taken together with the        nitrogen to which they are attached to form a substituted or        unsubstituted heterocyclyl; and    -   b. C₂₋₉ heteroaryl or C₆₋₁₀ aryl, wherein said heteroaryl has        1-4 heteroatoms selected from O, S and N; and wherein said aryl        and heteroaryl can be optionally substituted with one, two,        three or four substituents selected from the group consisting of        branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene,        C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl, hydroxyl, halogen, —CHF₂,        —CF₃, amino, di(C₁₋₆ alkyl)amino, mono(C₁₋₆ alkyl)amino, cyano,        C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′, —SO₂NR′R″, —C(O)NR′R″, and        —NR′C(O)R″, wherein R′ and R″ are independently H or C₁₋₆ alkyl;        or

iii. C₁₋₆ alkyl optionally substituted with one to four substituentsindependently selected from the group consisting of hydroxyl, halogen,cyano, C₁₋₆ alkoxy, amino, mono(C₁₋₆ alkyl)amino, di(C₁₋₆ alkyl)amino,C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 5-10 memberedheterocyclyl, —SO₂R′, —SO₂NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″,—NR′C(O)NR″R′″, —NR′SO₂NR″R′″ and —NR′S(O)R″;

-   -   wherein R′ and R′″ are independently H or C₁₋₆ alkyl and R″ is        independently C₁₋₆ alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl        optionally substituted with C₁₋₆ alkyl; or R″ and R′″ are taken        together with the nitrogen to which they are attached to form an        optionally substituted C₃₋₇ heterocyclyl.

In some embodiments, A is C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, or C₂₋₉heterocyclyl, wherein said cycloalkyl, heteroaryl, or heterocyclyl canbe optionally substituted with one, two, three or four of R₅, wherein R₅is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenylene, halogen, cyano, hydroxyl,C₁₋₆ alkoxy, optionally substituted C₂₋₉ heteroaryl, —SO₂R^(e),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)SO₂R^(f) and NR^(e)R^(f)—C(O)—;wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyleneof R₅ can be optionally substituted with one to four substituentsindependently selected from the group consisting of C₁₋₆ alkoxy,hydroxyl, halogen, cyano, —SO₂R^(e), —NR^(e)R^(f), —NR^(e)C(O)R^(f) and—C(O)NR^(e)R^(f), wherein R^(e) and R^(f) in each occurrence areindependently selected from the group consisting of hydrogen, branchedor linear C₁₋₆ alkyl and C₃₋₇ cycloalkyl; or, said cycloalkyl orheterocyclyl together with two of R₅ form a bicyclic or spiro ring,wherein two of R₅ attached to different atoms are taken together withthe carbon to which each is attached to form a bicyclic, or two of R₅attached to the same carbon are taken together with the carbon to whicheach is attached to form a spiro ring.

In some embodiments, A is optionally substituted C₃₋₇ cycloalkyl.

In some embodiments, A is C₁₋₆ alkyl optionally substituted with one tofour substituents independently selected from the group consisting ofhydroxyl, halogen, cyano, C₁₋₆ alkoxy, amino, mono(C₁₋₆ alkyl)amino,di(C₁₋₆ alkyl)amino, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, —SO₂R′, —SO₂NR′R″,—C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′C(O)NR″R′″, —NR′SO₂NR″R′″ or—NR′S(O)R″, wherein R′ and R′″ are independently H or C₁₋₆ alkyl and R″is independently C₁₋₆ alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl optionallysubstituted with C₁₋₆ alkyl; or R″ and R′″ are taken together with thenitrogen to which they are attached to form a substituted orunsubstituted heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl are optionallysubstituted (e.g., with one to four substituents independently selectedfrom the group consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy).

Useful values of R₅ are described above. In an embodiment, R₅ isselected from the group consisting of hydrogen, fluoro, cyano,NH₂—C(O)—, C₂₋₉ heteroaryl, cyano(C₁₋₆)alkyl, and hydroxyl(C₁₋₆)alkyl,and all other variables are as described in Formula I or Ia or are asdescribed in any of the embodiments described herein. In particularaspects of this embodiment, R₅ is fluoro or cyano and all othervariables are as described in Formula I or Ia or are as described in anyof the embodiments described herein.

In an embodiment, R₅ is C₂₋₉ heteroaryl. In particular aspects of thisembodiment, the C₂₋₉ heteroaryl is an optionally substituted heteroarylcontaining at least one nitrogen. In particular aspects of thisembodiment, the heteroaryl is an optionally substituted 5-memberheteroaryl containing 1 or 2 nitrogen atoms. In particular aspects ofthis embodiment, the 5-member heteroaryl is an optionally substitutedpyrazole.

In an embodiment, at least one R₅ is cyano(C₁₋₆)alkyl. In particularaspects of this embodiment, at least one R₅ is cyano-CH₂—.

In an embodiment, R₅ is hydrogen.

In an embodiment, R₅ is a group described above other than hydrogen, andall other variables are as described in Formula I or Ia or are asdescribed in any of the embodiments described herein.

In an embodiment where R₅ is other than hydrogen, R₄ is A-C(O)—,wherein, A is:

where, v is zero, one, two, three or four; X, Y and Z are eachindependently absent or —CH₂—, and wherein, if present, zero, one or twoof H on each of X, Y and Z can be R₅; and all other variables are asdescribed in Formula I or Ia or are as described in any of theembodiments described herein.

In an embodiment, A is

where, v is zero, one or two, and all other variables are as defined inFormula I or Ia or are as described in any of the embodiments describedherein.

In an embodiment, A is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described above.

In an embodiment, R₅ is other than hydrogen and R₄ is A-C(O)—, wherein,A is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described above.

In an embodiment, A is

where, v is zero, one or two, and all other variables are as defined inFormula I or Ia or are as defined in any of the embodiments describedabove.

In an embodiment, R₅ is other than hydrogen and R₄ is A-C(O)—, wherein,A is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described above.

In some embodiments, R₄ is

wherein, v is 0, 1, 2 or 3; and R₅ is selected from the group consistingof C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenylene, halogen,cyano, hydroxyl, C₁₋₆ alkoxy, optionally substituted C₂₋₉ heteroaryl,—SO₂R^(e), —NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)SO₂R^(f) andNR^(e)R^(f)—C(O)—; wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkenylene of R₅ can be optionally substituted with one tofour substituents independently selected from the group consisting ofC₁₋₆ alkoxy, hydroxyl, halogen, cyano, —SO₂R^(e), —NR^(e)R^(f),—NR^(e)C(O)R^(f) and —C(O)NR^(e)R^(f), wherein R^(e) and R^(f) in eachoccurrence are independently selected from the group consisting ofhydrogen, branched or linear C₁₋₆ alkyl and C₃₋₇ cycloalkyl.

In embodiments where all other variables are as defined in anyembodiment above, R₅ is selected from the group consisting of hydrogen,fluorine, cyano, NH₂—C(O)—, alkyl-(C₁₋₆)alkoxy-, optionally substitutedC₂₋₉ heteroaryl, and cyano(C₁₋₆)alkyl. In these embodiments, R₅ isfluoro or cyano. In these embodiments, R₅ is hydrogen. In theseembodiments, R₅ is optionally substituted C₂₋₉ heteroaryl orcyano(C₁₋₆)alkyl. In these embodiments, R₅ is cyano-CH₂—. In someembodiments, at least one R₅ is C₁₋₆ alkyl (e.g., methyl).

In embodiments where all other variables are as defined in anyembodiment above, the compound wherein at least one R₅ is optionallysubstituted C₂₋₉ heteroaryl.

In embodiments where all other variables are as defined in anyembodiment above, the compound wherein the at least one R₅ is optionallysubstituted C₂₋₉ heteroaryl is an optionally substituted 5-memberheteroaryl containing 1 or 2 nitrogen atoms.

In embodiments where all other variables are as defined in anyembodiment above, the compound wherein the optionally substituted5-member heteroaryl is an optionally substituted pyrazole.

In embodiments where all other variables are as defined in anyembodiment above, the compound wherein the optionally substitutedpyrazole is

wherein the wavy line denotes the point of attachment to the cyclopropylring; and wherein R′ is branched or linear C₁₋₆ alkyl, wherein the alkylcan be optionally substituted with one to four hydroxyl, halogen,nitrile, amino, —O—(C₁₋₆)alkyl, —O—(C₁₋₆)alkylamino-,di(C₁₋₆)alkylamino-, or —NR^(y)(CO)R^(z), wherein R^(y) and R^(z), ineach instance, is independently hydrogen or C₁₋₆ alkyl; or —SO₂R′,wherein R′ is C₁₋₆ alkyl.

In embodiments where all other variables are as defined in anyembodiment above, the compound wherein R^(B1) is optionally substitutedlinear C₁₋₆ alkyl.

In embodiments where all other variables are as defined in anyembodiment above, the compound wherein the optionally substituted linearC₁₋₆ alkyl is methyl.

In some embodiments, R₄ is

wherein v is 2, one R₅ is methyl and the second R₅ is1-methylpyrazol-4-yl.

In some embodiments, R₄ is

In some embodiments, R₄ is

In some embodiments, R₄ is

In some embodiments, R₄ is

In some embodiments, R₄ is

In some embodiments, the compound of Formula I or Ia is selected fromCompound Nos. 195, 196, 197, 198, 279, 280, 281, 282 and 358, or apharmaceutically acceptable salt thereof.

In some embodiments, R₄ is A-C(O)—, wherein A is —NHR^(g) or —OR^(h),wherein R^(g) and R^(h) are independently C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆alkenylene, C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl or C₆₋₁₀aryl; each of which can be optinally substituted as detailed herein. Insome embodiments, R^(g) and R^(h) are independently selected from thegroup consisting of:

a. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₂₋₉heterocyclyl, and C₃₋₇ cycloalkyl, wherein said alkyl, alkenyl,alkenylene, heterocyclyl and cycloalkyl can be optionally substitutedwith one to four substituents independently selected from the groupconsisting of hydroxyl, halogen, —CHF₂, —CF₃, amino, di(C₁₋₆alkyl)amino, mono(C₁₋₆ alkyl)amino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,—SO₂R′, —SO₂NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′C(O)NR″R′″,—NR′SO₂NR″R′″ or —NR′S(O)R″, wherein R′ and R′″ are independently H orC₁₋₆ alkyl and R″ is independently C₁₋₆ alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀aryl optionally substituted with C₁₋₆ alkyl; or R″ and R′″ are takentogether with the nitrogen to which they are attached to form asubstituted or unsubstituted heterocyclyl; and

b. C₂₋₉ heteroaryl or C₆₋₁₀ aryl, wherein said heteroaryl has 1-4heteroatoms selected from O, S and N; and wherein said aryl andheteroaryl can be optionally substituted with one, two, three or foursubstituents selected from the group consisting of branched or linearC₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, C₃₋₇cycloalkyl, hydroxyl, halogen, —CHF₂, —CF₃, amino, di(C₁₋₆ alkyl)amino,mono(C₁₋₆ alkyl)amino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′,—SO₂NR′R″, —C(O)NR′R″, and —NR′C(O)R″, wherein R′ and R″ areindependently H or C₁₋₆ alkyl.

In embodiments, R₄ is A-C(O)—, wherein, A is: ii. —NHR^(g), whereinR^(g) is selected from the group consisting of: a. branched or linearC₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, and C₃₋₇cycloalkyl, wherein said alkyl, alkenyl, alkenylene, heterocyclyl andcycloalkyl can be optionally substituted with hydroxyl, halogen, —CF₂,—CF₃, amino, di(C₁₋₆)alkylamino, mono(C₁₋₆)alkylamino, cyano, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, —SO₂R′, —SO₂NR′R″, —(CO)NR′R″, or —NR′(CO)R″,wherein R′ and R″ are independently H or C₁₋₆ alkyl; and b. C₂₋₉heteroaryl or C₆₋₁₀ aryl, wherein said heteroaryl has 1-4 heteroatomsselected from O, S and N; and wherein said aryl and heteroaryl can beoptionally substituted with one, two, three or four substituentsselected from the group consisting of branched or linear C₁₋₆ alkyl,C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl,hydroxyl, halogen, —CF₂, —CF₃, amino, di(C₁₋₆)alkylamino,mono(C₁₋₆)alkylamino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′,—SO₂NR′R″, —(CO)NR′R″, and —NR′(CO)R″, wherein R′ and R″ areindependently H or C₁₋₆ alkyl, and all other variables are as describedin Formula I or Ia or are as described in any of the embodiments herein.

In embodiments where all other variables are as defined in anyembodiment above, R₂ is D. In some embodiments, D is a 5-10 memberedheteroaryl, having 1-4 heteroatoms selected from O, S, and N; andoptionally substituted with one, two, three or four substituents,wherein two of the substituents attached to different atoms are takentogether with the atom to which each is attached to form a bicyclic ortricyclic, wherein said bicyclic or tricyclic is optionally substituted;or the 5-10 membered heteroaryl is fused with a ring selected from thegroup consisting of 5 or 6 membered heteroaryl, 5-10 memberedheterocyclyl, C₆ aryl and C₃₋₈ cycloalkyl, wherein the 5-10 memberedheteroaryl of D and the fused ring are optionally substituted, whereinsaid fused ring forms an optionally substituted bicyclic or tricyclicsystem.

In some embodiments, D is hydrogen or a 5-10 membered heteroaryl, having1-4 heteroatoms selected from O, S, and N; and optionally substituted(e.g., with one, two, three or four substituents independently selectedfrom the group consisting of hydroxyl, oxo, C₁₋₆ alkyl and C₁₋₆ alkoxy);or 5-10 membered heteroaryl fused with a ring selected from the groupconsisting of 5 or 6 membered heteroaryl, 5-10 membered heterocyclyl, C₆aryl and C₃₋₈ cycloalkyl, wherein the 5-10 membered heteroaryl of D andthe fused ring are optionally substituted (e.g., with one to foursubstituents independently selected from the group consisting ofhydroxyl, oxo, C₁₋₆ alkyl and C₁₋₆ alkoxy).

In an embodiment, R₄ is D, wherein, D is an optionally substitutedheteroaryl containing at least one nitrogen. In embodiments, theheterocyclyl is an optionally substituted 5-member heterocyclylcontaining 1 or 2 nitrogen atoms. In embodiments, the 5-memberheterocyclyl is an optionally substituted pyrazole.

In an embodiment, the optionally substituted pyrazole is wherein thewavy line denotes the point of attachment to the N; and wherein R^(A) isbranched or linear C₁₋₆ alkyl, wherein said alkyl can be optionallysubstituted with one to four hydroxyl, halogen, nitrile, amino,mono(C₁₋₆)alkylamino-, di(C₁₋₆)alkylamino-, or —NR^(y)(CO)R^(z), whereinR^(y) and R^(z), in each instance, is independently hydrogen or C₁₋₆alkyl.

In an embodiment, R^(A) is linear C₁₋₆ alkyl substituted with hydroxyl,halogen, nitrile, or amino.

In an embodiment, the linear C₁₋₆ alkyl is ethyl substituted withnitrile.

In an embodiment, R^(A) is

In an embodiment, R^(A) is

In some embodiments, the optionally substituted pyrazole is fused withanother cyclic moiety to form an optionally substituted bicyclic ortricyclic, e.g., a 3-pyrozolyl having another cyclic moiety fused to the1,5 bond. In some embodiments, D is a bicyclic (or tricyclic wherefurther ring fusion is present) which is

wherein X′ and Y′ are each independently C, N, S, or O; and wherein saidbicyclic is optionally substituted with one, two, three or foursubstituents independently selected from the group consisting ofhydrogen, hydroxyl, amino and C₁₋₆ alkyl; and wherein two of thesubstituents taken together with the atoms to which they are attachedcan form a C₃-C₅ spiro or a C₂₋₉ heteroaryl ring; wherein said C₂₋₉heteroaryl ring may be fused to said bicyclic to form a tricyclic. Insome of these embodiments, at least one of X′ or Y′ are N.

In some embodiments, D is

In some embodiments, the compound of Formula I or Ia is selected fromCompound Nos. 228, 229, 230, 247, 276, 315 and 316, or apharmaceutically acceptable salt thereof

In embodiments where all other variables are as defined in anyembodiment detailed herein, the compound wherein D is is a 5-memberedheteroaryl having the formula

or a 6-membered heteroaryl having the formula

wherein:

Q is NR²⁰, CR²⁰, O or S;

each T is independently N or CR²¹;

each Z is independently N or C, provided that only one Z is N;

each R²⁰ and R²¹ is independently hydrogen, alkyl, haloalkyl, alkoxy,halogen, hydroxy, or cyano; and

R²² and R²³ are taken together with the atoms to which they are attachedto form a bicyclic; wherein the bicyclic may contain one or moreheteroatoms selected from N, S and O; and wherein the bicyclic isoptionally substituted with one, two, three, four or five R³⁰;

wherein each R³⁰ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, C₃₋₇ heterocyclyl, halogen, cyano, oxo, —NR³¹R³²,—SO₂NR³¹R³², —C(O)NR³¹R³², —C(O)OR³³, —OR³³, —NR³³C(O)R³⁴, —NR³³SO₂R³⁵or —SO₂R³⁵; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl andC₃₋₇ heterocyclyl of R³⁰ are optionally substituted with one to fourR⁴⁰; or two R³⁰ groups are taken together with the parent moiety to withthey are attached to form a ring which is optionally substituted withone to four R⁴⁰;

each R³¹ and R³² is independently hydrogen or C₁₋₆ alkyl; or R³¹ and R³²are taken together with the nitrogen atom to which they are attached toform a C₃₋₇ heterocyclyl optionally substituted with one to four R⁴⁰;

each R³³ and R³⁴ are independently hydrogen or C₁₋₆ alkyl;

R³⁵ is C₁₋₆ alkyl;

each R⁴⁰ is independently selected from the group consisting of halogen,cyano, oxo, —NR₄₁R₄₂, —SO₂NR⁴¹R⁴², —C(O)NR⁴¹R⁴², —C(O)OR₄₃,—NR⁴³C(O)R⁴⁴, —NR⁴³SO₂R⁴⁵ or —SO₂R⁴⁵; C₁₋₆ alkyl, C₁₋₆ haloalkyl [e.g.,—CHF₂, or —CF₃], C₂₋₉ heteroaryl, C₆₋₁₀ aryl, oxo; or two R⁴⁰ groups aretaken together with the parent moiety to with they are attached to forma ring which is optionally substituted with one to three substituentsselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl and oxo;

each R⁴¹ and R⁴² is independently hydrogen or C₁₋₆ alkyl; or R⁴¹ and R⁴²are taken together with the nitrogen atom to which they are attached toform a C₃₋₇ heterocyclyl optionally substituted with one to threesubstituents selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl and oxo;

each R⁴³ and R⁴⁴ are independently hydrogen or C₁₋₆ alkyl; and

R⁴⁵ is C₁₋₆ alkyl.

In some embodiments, D is:

wherein q is 0, 1, 2, 3, 4, 5 or 6; R³⁶ is independently hydrogen orR³⁰; and R²⁰ and R³⁰ are as detailed herein. In some of theseembodiments, R²⁰ is hydrogen, C₁₋₆ alkyl (e.g., methyl), halogen (e.g.,fluoro), hydroxyl, or C₁₋₆ alkoxy (e.g., methoxy). In some embodiments,R²⁰ is H, Me, F or OH. In some of these embodiments, R³⁶ is hydrogen orC₁₋₆ alkyl (e.g., methyl). In some of these embodiments, q is 0.

In some embodiments, D is:

wherein q is 0, 1, 2, 3, 4, 5 or 6; and R²⁰ and R³⁰ are as detailedherein. In some of these embodiments, q is 0. In some of theseembodiments, R²⁰ is hydrogen, C₁₋₆ alkyl (e.g., methyl), halogen (e.g.,fluoro), hydroxyl, or C₁₋₆ alkoxy (e.g., methoxy). In some embodiments,R²⁰ is H, Me, F or OH.

In some embodiments, D is:

wherein R³⁶ is independently hydrogen or R³⁰; and R²⁰ and R³⁰ are asdetailed herein. In some embodiments, R³⁶ is hydrogen or C₁₋₆ alkyl(e.g., methyl); and R²⁰ is hydrogen.

In some embodiments, wherein D is

wherein p is 0, 1, 2, 3 or 4; R³⁶ is independently hydrogen or R³⁰; andR²⁰ and R³⁰ are as detailed herein. In some embodiments, p is 0. In someembodiments, R³⁶ is hydrogen or C₁₋₆ alkyl (e.g., methyl); and R²⁰ ishydrogen.

In some embodiments, wherein D is

wherein X is CH2, N, O or S; n is 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4;R³⁶ is hydrogen or R³⁰; and R²⁰ and R³⁰ are as detailed herein. In someof these embodiments, X is CH2 and n is 1. In some embodiments, R³⁶ ishydrogen or C₁₋₆ alkyl (e.g., methyl); and R²⁰ is hydrogen.

In some embodiments, wherein D is

wherein q is 0, 1, 2, 3, 4, 5 or 6; G is independently C or N; G′ isindependently N, NR⁴⁶, CR⁴⁷, S or O; R⁴⁶ and R⁴⁷ are independentlyhydrogen or R⁴⁰, and R²⁰ and R⁴⁰ are as detailed herein. In someembodiments, two groups R⁴⁶ and R⁴⁷ are taken together to form a ring.In some of these embodiments, one of G is C and the other one of G is N.In some embodiments, each G is C. In some embodiments, at least one ofG′ is N. In some embodiments, at least one of G′ is CR⁴⁷. In someembodiments, R⁴⁷ is H. In some embodiments, R²⁰ is hydrogen.

In some embodiments, wherein D is

wherein R²⁰ and R⁴⁶ are as detailed herein. In some embodiments, R⁴⁶ ishydrogen or C₁₋₆ alkyl (e.g., methyl); and R²⁰ is hydrogen.

In some embodiments, wherein D is

In some embodiments, wherein D is

wherein Q is NR²⁰, O or S; X is CR^(38a)R^(38b), NR³⁶, S or O; X′ isCR^(39a)R^(39b), NR³⁶, S, SO₂ or O; R³⁶, R^(37a), R^(37b), R^(38a) andR^(38b) are independently hydrogen or R³⁰; R^(39a) and R^(39b) areindependently hydrogen or R³⁰, or R^(39a) and R^(39b) are taken togetherwith the carbon atom to which they are attached to form a C₃₋₇cycloalkyl or C₃₋₇ heterocyclyl; and R²⁰ and R³⁰ are as detailed herein.In some of these embodiments, Q is NR²⁰. In some of these embodiments, Qis S. In some embodiments, X is CH₂ or NR³⁶. In some embodiments, X′ isCH₂. In some embodiments, X′ is SO₂. In some embodiments, X′ isCR^(39a)R^(39b) where R^(39a) and R^(39b) are taken together with thecarbon atom to which they are attached to form a cyclopropyl. In someembodiments, R³⁶ is hydrogen or C₁₋₆ alkyl (e.g., methyl); and R²⁰ ishydrogen.

In some embodiments, wherein D is

wherein X, X′, R²⁰ and R³⁶ are as detailed herein. In some of theseembodiments, X is CH₂ or NR³⁶. In some embodiments, X′ is CH₂. In someembodiments, X′ is SO₂. In some embodiments, X′ is CR^(39a)R^(39b) whereR^(39a) and R^(39b) are taken together with the carbon atom to whichthey are attached to form a cyclopropyl. In some embodiments, R³⁶ ishydrogen or C₁₋₆ alkyl (e.g., methyl). In some embodiments, R²⁰ ishydrogen.

In some aspects in the compound of Formula I or Ia, R₂ is:

(a) a C₆₋₁₀ aryl, 5-10 membered heteroaryl or 5-10 memberedheterocyclyl, having 1-4 heteroatoms selected from O, S, and N; andoptionally substituted with one, two, three or four substituents, R₆,R₇, R₅ and R_(8′), each of which is independently selected from thegroup consisting of:

-   -   i. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆        alkenylene, wherein said alkyl, alkenyl and alkenylene can be        optionally substituted with one to four substituents        independently selected from the group consisting of hydroxyl,        halogen, nitrile, amino, mono(C₁₋₆alkyl)amino-,        di(C₁₋₆alkyl)amino-, —SO₂R^(y), —S(O)NR^(y), —(CO)NR^(y)R^(z),        —NR^(z)SO₂R^(y), —NR^(y)(CO)OR^(z), —NR^(y)(CO)NR^(y)R^(z), and        —NR^(y)(CO)R^(z), wherein R^(y) and R^(z), in each instance, is        independently hydrogen or optionally substituted C₁₋₆ alkyl        (e.g., an alkyl optionally substituted with one to four        substituents independently selected from the group consisting of        hydroxyl and halogen);    -   ii. NR^(y)R^(z)—C(O)—, wherein R^(y) and R^(z) are each        independently hydrogen or optionally substituted C₁₋₆ alkyl        (e.g., an alkyl optionally substituted with one to four        substituents independently selected from the group consisting of        hydroxyl and halogen);    -   iii. hydroxy(C₁₋₆ alkyl);    -   iv. hydroxyl or optionally substituted C₁₋₆ alkoxy (e.g., an        alkoxy optionally substituted with one to four substituents        independently selected from the group consisting of hydroxyl and        halogen);    -   v. substituted or unsubstituted C₃₋₉ cycloalkyl, substituted or        unsubstituted C₆ aryl, substituted or unsubstituted 5-membered        heteroaryl, or substituted or unsubstituted C₂₋₉ heterocyclyl;    -   vi. halogen;    -   vii. substituted or unsubstituted amino;    -   viii. cyano;    -   ix. —NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are each        independently hydrogen or optionally substituted C₁₋₆ alkyl        (e.g., an alkyl optionally substituted with one to four        substituents independently selected from the group consisting of        hydroxyl and halogen);    -   x. —SO₂R′, wherein R′ is H or C₁₋₆ alkyl;    -   xi. —SO₂NR′R″, wherein R′ and R″ are independently H or C₁₋₆        alkyl; or R′ and R″ are taken together with the nitrogen to        which they are attached to form a substituted or unsubstituted        heterocyclyl;    -   xii. —NR′C(O)OR″, —NR′C(O)NR″R′″, —NR′SO₂NR″R′″ or —NR′S(O)R″,        wherein R′ and R′″ are independently H or C₁₋₆ alkyl and R″ is        independently C₁₋₆ alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl        optionally substituted with C₁₋₆ alkyl; or R″ and R′″ are taken        together with the nitrogen to which they are attached to form a        substituted or unsubstituted heterocyclyl; and    -   xiii. wherein a carbon embedded in said heterocyclyl taken        together with an oxygen to which it is bound can form a        carbonyl; or

(b) a C₆₋₁₀ aryl having one, two, three or five substituents selectedfrom the group consisting of branched or linear C₁₋₆ alkyl, C₁₋₆alkenyl, C₁₋₆ alkenylene, C₃₋₄ cycloalkyl, wherein said alkyl, alkenyl,alkenylene and cycloalkyl can be substituted with amino, hydroxyl,cyano, halogen, amide, mono(C₁₋₆ alkyl)amino-, di(C₁₋₆ alkyl)amino-,—SO₂R^(c), —S(O)NR^(d), —C(O)NR^(c)R^(d) and —NR^(c)C(O)R^(d),

wherein R^(c) and R^(d) are each independently selected from the groupconsisting of hydrogen and C₁₋₆ alkyl, wherein said alkyl can beoptionally substituted with one to four hydroxyl or halogen; or

(c) hydrogen, —NHSO₂R^(a), —SO₂NR^(a)R^(b); or —SO₂NH₂; wherein eachR^(a) is independently C₁₋₆ alkyl, and R^(b) is hydrogen or C₁₋₆ alkyl;or

(d) —OR^(a1) or —(C₁₋₆ alkyl)-OR^(a1); wherein each R^(a1) isindependently C₁₋₆ alkyl optionally substituted with C₆₋₁₀ aryl; 5-10membered heteroaryl; or 5-10 membered heterocyclyl; wherein the 5-10membered heteroaryl, and 5-10 membered heterocyclyl are optionallysubstituted with one to four substituents independently selected fromthe group consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or

(e) a C₁₋₆ alkyl optionally substituted with one to five substituentsindependently selected from the group consisting of hydroxyl, halogen,cyano, amino, mono(C₁₋₆ alkyl)amino, di(C₁₋₆ alkyl)amino, amido,sulfonyl, sulfonamide, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl; wherein the C₃₋₈ cycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl areoptionally substituted (e.g., with one to four substituentsindependently selected from the group consisting of hydroxyl, oxo, C₁₋₆alkyl or C₁₋₆ alkoxy); or

(f) C₃₋₈ cycloalkyl optionally substituted with one to four substituentsindependently selected from the group consisting of C₁₋₆ alkyl,hydroxyl, halogen, cyano, amino, mono(C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, amido, sulfonyl, sulfonamide, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl; wherein the 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl are optionally substituted(e.g., with one to four substituents independently selected from thegroup consisting of hydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy);

(g) —C(O)NR^(a2)R^(b2) or —SO₂NR^(a2)R^(b2), wherein each R^(a2) isindependently hydrogen or C₁₋₆ alkyl, and R^(b2) is hydrogen, C₁₋₆alkyl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, whereinthe 5-10 membered heteroaryl and 5-10 membered heterocyclyl areoptionally substituted (e.g., with one to four substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, oxo, hydroxyl, halo and cyano); or R^(a2) and R^(b2) aretaken together with the nitrogen to which they are attached to form asubstituted or unsubstituted heterocyclyl (e.g., piperidine, piperazine,pyrrolidine); or

(h) 5-10 membered heteroaryl fused with a ring selected from the groupconsisting of 5 or 6 membered heteroaryl, 5-10 membered heterocyclyl, C₆aryl and C₃₋₇ cycloalkyl, wherein the 5-10 membered heteroaryl of R₂ andthe fused ring are optionally substituted (e.g., with one to foursubstituents independently selected from the group consisting ofhydroxyl, oxo, C₁₋₆ alkyl or C₁₋₆ alkoxy).

In embodiments where all other variables are as defined above, usefulvalues of R₂ are an optionally substituted C₂₋₉ heteroaryl, or anoptionally substituted C₂₋₉ heterocyclyl (e.g., C₃₋₇ heterocyclyl). Inan embodiment, R₂ is an optionally substituted 5-10 member heteroaryl oran optionally substituted 5-10 member heterocyclyl; and all othervariables are as defined in Formula I or Ia or are as defined in any ofthe embodiments described herein. In an aspect of this embodiment, R₂ isa 5 member heteroaryl. In an aspect of this embodiment, R₂ is a 5 memberheterocyclyl. In an aspect of this embodiment, R₂ is a 6 memberheteroaryl. In an aspect of this embodiment, R₂ is a 6 memberheterocyclyl. In an aspect of this embodiment, R₂ is a 7 memberheteroaryl. In an aspect of this embodiment, R₂ is a 7 memberheterocyclyl. In an aspect of this embodiment, R₂ is an 8 memberheteroaryl. In an aspect of this embodiment, R₂ is an 8 memberheterocyclyl. In an aspect of this embodiment, R₂ is a 9 memberheteroaryl. In an aspect of this embodiment, R₂ is a 9 memberheterocyclyl. In an aspect of this embodiment, R₂ is a 10 memberheteroaryl. In an aspect of this embodiment, R₂ is a 10 memberheterocyclyl. In each instance, the heteroaryl or heterocyclyl can beoptionally substituted at with one, two or three substituents, R₆, R₇and R₈.

In some embodiments, R₆, R₇, and R₅ are each independently selected fromthe group consisting of:

-   -   i. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆        alkenylene, wherein said alkyl, alkenyl and alkenylene can be        optionally substituted with one to four substituents        independently selected from the group consisting of hydroxyl,        halogen, nitrile, amino, mono(C₁₋₆alkyl)amino-,        di(C₁₋₆alkyl)amino-, —SO₂R^(y), —S(O)NR^(y), —(CO)NR^(y)R^(z)        and —NR^(y)(CO)R^(z), wherein R^(y) and R^(z), in each instance,        is independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can        optionally be substituted with one to four substituents        independently selected from the group consisting of hydroxyl and        halogen;

ii. NR^(y)R^(z)—C(O)—, wherein R^(y) and R^(z) are each independentlyhydrogen or C₁₋₆ alkyl, wherein said alkyl can optionally be substitutedwith one to four substituents independently selected from the groupconsisting of hydroxyl and halogen;

iii. hydroxy(C₁₋₆ alkyl);

iv. C₁₋₆ alkoxy, wherein said alkoxy can be optionally substituted withone to four substituents independently selected from the groupconsisting of hydroxyl and halogen;

v. C₃₋₉ cycloalkyl, substituted or unsubstituted C₆ aryl, substituted orunsubstituted 5-membered heteroaryl, or C₂₋₉ heterocyclyl;

vi. halogen;

vii. amino;

viii. cyano;

ix. —NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are each independentlyhydrogen or C₁₋₆ alkyl, wherein said alkyl can optionally be substitutedwith one to four substituents independently selected from the groupconsisting of hydroxyl and halogen;

x. —SO₂R′, wherein R′ is H or C₁₋₆ alkyl;

xi. —SO₂NR′R″, wherein R′ and R″ are independently H or C₁₋₆ alkyl;

xii. —NR′C(O)OR″, —NR′SO₂NR″ or —NR′S(O)R″, wherein R′ is independentlyH or C₁₋₆ alkyl and R″ is independently C₁₋₆ alkyl, halo(C₁₋₆ alkyl) orC₆₋₁₀ aryl optionally substituted with C₁₋₆ alkyl; and

xiii. wherein a carbon embedded in said heterocyclyl taken together withan oxygen to which it is bound can form a carbonyl.

In an embodiment, R₂ is selected from the group consisting of:

each of which is optionally substituted. In some embodiments, each ofthe above moieties can be optionally substituted with one, two or threesubstituents, R₆, R₇ and R₈; and all other variables are as defined inFormula I or Ia or are as defined in any of the embodiments describedherein.

In some embodiments, R₂ is selected from the group consisting of:

each of which is optionally substituted. In some embodiments, each ofthe above moieties can be optionally substituted with one, two or threesubstituents, R₆, R₇ and R₈; and all other variables are as defined inFormula I or Ia or are as defined in any of the embodiments describedherein.

In embodiments where all other variables are as defined in anyembodiment above, useful values of R₂ are

In embodiments where all other variables are as defined in anyembodiment above, R₂ is

In embodiments where all other variables are as defined in anyembodiment above, wherein R₂ is

In embodiments where all other variables are as defined in anyembodiment above, wherein R₂ is

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In some embodiments, R₂ is wherein R₆, R₇, and R₅ are each independentlyselected from the group consisting of hydrogen, hydroxyl, amino, C₁₋₆alkyl, C₁₋₆ alkoxy, and mono(C₁₋₆ alkyl)amino; or two of R₆, R₇, and R₅can form a bicyclic.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In some of theseembodiments, R₆ and R₇ are selected from the group consisting ofhydrogen, amino, and C₁₋₆ alkyl. In some embodiments, R₆ is C₁₋₆ alkyl(e.g., methyl). In some embodiments, R₇ is hydrogen or amino. In someembodiments, R₇ is hydrogen. In some embodiments, R₇ is amino. In someembodiments, R₆ is C₁₋₆ alkyl (e.g., methyl) and R₇ is hydrogen oramino.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In this embodiment,R₆ can be hydrogen, optionally substituted C₁₋₆ alkyl orhydroxy(C₁₋₆)alkyl, and all other variables are as defined in Formula Ior Ia or are as defined in any of the embodiments described herein. Inan aspect of this embodiment, R₆ can be C₁₋₆ alkyl, such as methyl,ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, and hexyl, and allother variables are as defined in Formula I or Ia or are as defined inany of the embodiments described herein. In a particular aspect of thisembodiment, R₆ is methyl and all other variables are as defined inFormula I or Ia or are as defined in any of the embodiments describedherein. In some of these embodiments, R₆ is C₁₋₆ alkyl, optionallysubstituted with hydroxyl, —CF₂, —CF₃, or halogen.

In some embodiments, R₂ is

In some embodiments, R₂ is

In some embodiments, R₂ is

In some embodiments, R₂ is

In some embodiments, R₂ is

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described above. In this embodiment,R₆ can be optionally substituted branched or linear C₁₋₆ alkyl, whichcan be substituted with one to four hydroxyl or halogen; and all othervariables are as defined in Formula I or Ia or are as defined in any ofthe embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In this embodiment,R₆ can be optionally substituted branched or linear C₁₋₆ alkyl; and allother variables are as defined in Formula I or Ia or are as defined inany of the embodiments described herein. In an aspect of thisembodiment, R₆ can be C₁₋₆ alkyl, such as methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl, pentyl, and hexyl, and all other variablesare as defined in Formula I or Ia or are as defined in any of theembodiments described herein. In a particular aspect of this embodiment,R₆ is methyl and all other variables are as defined in Formula I or Iaor are as defined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In a particularaspect of this embodiment, R₆ can be optionally substituted branched orlinear C₁₋₆ alkyl; and all other variables are as defined in Formula Ior Ia or are as defined in any of the embodiments described herein. Inan aspect of this embodiment, R₆ can be C₁₋₆ alkyl, such as methyl,ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, and hexyl, and allother variables are as defined in Formula I or Ia or are as defined inany of the embodiments described herein. In a particular aspect of thisembodiment, R₆ is methyl and all other variables are as defined inFormula I or Ia or are as defined in any of the embodiments describedherein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In a particularaspect of this embodiment, R₆ can be hydrogen or optionally substitutedbranched or linear C₁₋₆ alkyl, R₇ can be hydrogen or optionallysubstituted branched or linear C₁₋₆ alkyl, and all other variables areas defined in Formula I or Ia or are as defined in any of theembodiments described herein. In an aspect of this embodiment, R₆ can beC₁₋₆ alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,pentyl, and hexyl, and all other variables are as defined in Formula Ior Ia or are as defined in any of the embodiments described herein. In aparticular aspect of this embodiment, R₆ is methyl and all othervariables are as described in Formula I or Ia or are as defined in anyof the embodiments described herein. In a particular aspect of thisembodiment, R₆ and R₇ are each hydrogen and all other variables are asdefined in Formula I or Ia or are as defined in any of the embodimentsdescribed herein. In a particular aspect of this embodiment, R₅ ishydrogen, and all other variables are as defined in Formula I or Ia orare as defined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein.

In an embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described above. In this embodiment,R₆ can be optionally substituted branched or linear C₁₋₆ alkyl, whichcan be substituted with one to four hydroxyl or halogen; and all othervariables are as defined in Formula I or Ia or are as defined in any ofthe embodiments described herein. In an aspect of this embodiment, R₆can be C₁₋₆ alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl,t-butyl, pentyl, and hexyl, and all other variables are as defined inFormula I or Ia or are as defined in any of the embodiments describedherein. In a particular aspect, R₆ is methyl.

In an embodiment, in a 5-10 member heterocyclyl, one of R₆, R₇ and R₅ isO and together with the carbon to which it is attached forms a carbonyl;and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In a particularaspect of this embodiment, R₂ is

wherein, R₇ is hydrogen or C₁₋₅ alkyl; and all other variables are asdefined in Formula I or Ia or are as defined in any of the embodimentsdescribed herein.

In an embodiment, in a 5-10 member heterocyclyl, one of R₆, R₇ and R₅ isO and together with the carbon to which it is attached forms a carbonyl;and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In a particularaspect of this embodiment, R₂ is

and all other variables are as defined in Formula I or Ia or are asdefined in any of the embodiments described herein. In this embodiment,R₇ and R₅ are independently selected from hydrogen or branched or linearC₁₋₆ alkyl, which can be substituted with one to four hydroxyl orhalogen; and all other variables are as defined in Formula I or Ia orare as defined in any of the embodiments described herein.

In embodiments, the subject matter described herein is directed to acompound having one of the following structures:

In an embodiment, where all other variables are as defined in anyembodiment above, provided are compounds including any of compoundnumbers 1, 2, 3, 4, 5, 6, 7, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 30, 31, 32, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 59, 60, 61, 62, 63, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,104, 105, 106, 107, 108, 109, 110, 113, 115, 116, 117, 118, 119, 122,123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134, 135, 136, 137,138, 139, 140, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154,155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169,170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183,184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211,212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225,and 226.

In some embodiments, the disclosure provides a compound of formula I orIa, or a pharmaceutically acceptable salt thereof, wherein the compoundis selected from the group consisting of one or more compounds in Table1, Table 2 and/or Table 3. In some embodiments, the compound is selectedfrom Compound Nos. 9-12, 29, 33-36, 53, 58, 64, 83, 84, 96, 97, 111,112, 114, 120, 121, 129, 137, 141, 142, 152 and 158 in Table 1, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from Compound Nos. 231-390 in Table 2, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from Compound Nos. 391-528 in Table 3, or apharmaceutically acceptable salt thereof.

TABLE 1 Compound No. Structure Name  1

trans-N-[8-amino-6-(4-cyano-2- methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropane-1-carboxamide  2

N-(8-amino-6-(4-methylpyridin-3- yl)isoquinolin-3-yl)cyclopropanecarboxamide  3

cis-N-[8-amino-6-[4- (hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro- cyclopropane-1-carboxamide  4

N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide  5

N-(8-amino-7-cyano-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide  6

N-(8-amino-7-cyano-6-(1-methyl- 1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide  7

N-(8-amino-7-chloroisoquinolin- 3-yl)cyclopropanecarboxamide  8

N-(8-amino-7-cyanoisoquinolin- 3-yl)cyclopropanecarboxamide  13

5-[8-amino-3-[(cis-2- fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4- dimethyl-pyrimidine-2- carboxamide  14

cis-N-(8-amino-6-(6-methyl- 1H-benzo[d]imidazol-5-yl)isoquinolin-3-yl)-2-fluoro- cyclopropane-1-carboxamide  15

cis-N-(8-amino-6-(5- cyclopropylpyridazin-4- yl)isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  16

cis-N-(8-amino-6-(7- methyl-3H-imidazo[4,5-b]pyridin-6-yl)isoquinolin-3- yl)-2-fluorocyclopropane- 1-carboxamide  17

cis-N-(8-amino-6-(5- isopropyl-1H-pyrazol-4-yl) isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  18

cis-N-(8-amino-6-(1-ethyl-5- methyl-2-oxo-1,2-dihydro-pyridin-4-yl)isoquinolin-3-yl)- 2-fluorocyclopropane-1- carboxamide  19

cis-N-(8-amino-6-(5-methyl- 2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)-2- fluorocyclopropane-1- carboxamide  20

1-(8-amino-6-(1-methyl-1H- pyrazol-4-yl)isoquinolin-3-yl)-3-isopropylurea  21

trans--N-[8-amino-6-(1- methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano- cyclopropane-1-carboxamide  22

trans-N-[8-amino-6-(1H- pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano- cyclopropane-1-carboxamide  23

trans-N-[8-amino-6-(3-ethyl- 1-methyl-6-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano- cyclopropane-1-carboxamide  24

cis-N-[8-amino-6-(1,4- dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro- cyclopropane-1-carboxamide  25

trans-N-[8-amino-6-(1,4- dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclo- propane-1-carboxamide  26

cis-N-(8-amino-6-(6-methoxy- 2-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluoro- cyclopropane-1-carboxamide  27

cis-N-(8-amino-6-(2-methyl- 6-oxo-1,6-dihydropyridin-3-yl)isoquinolin-3-yl)-2-fluoro- cyclopropane-1-carboxamide  28

cis-N-(8-amino-6-(5-methyl- 1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  30

(1S,2S)-N-(8-amino-6-(5- oxopyrrolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  31

cis-N-(8-amino-6-(4-ethyl-6- (hydroxymethyl)pyridin-3-yl)isoquinolin-3-yl)-2- fluorocyclopropane-1- carboxamide  32

trans-N-(8-amino-6-(4- methylpyridin-3-yl) isoquinolin-3-yl)-2-cyano-cyclopropane-1-carboxamide  37, 108

(1S,2S)-N-(8-amino-6-(4- methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluoro- cyclopropane-1-carboxamide  38

trans-N-(8-amino-6-(quinolin- 4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide  39

cis-N-(8-amino-6-(5-amino- 4-ethylpyridin-3-yl) isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  40

3-amino-N-(8-amino-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)propanamide  41

cis-N-(8-amino-6-(5-isopropyl- 1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluoro cyclopropane-1- carboxamide  42

trans-N-(8-amino-6-(5-isopropyl- 1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  43

cis-N-(8-amino-6-(1-methyl-6- oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclo- propane-1-carboxamide  44

trans-N-[8-amino-6-(6-methyl- 1H-indazol-5-yl)-3- isoquinolyl]-2-cyano-cyclopropane-1-carboxamide  45

trans-N1-[8-amino-6-(6- methyl-1H-indazol-5-yl)-3-isoquinolyl]cyclopropane-1,2- dicarboxamide  46

cis-N-(8-amino-6-(4- methoxypyridin-3-yl) isoquinolin-3-yl)-2-fluoro-cyclopropane-1-carboxamide  47

trans-N-(8-amino-6-(4- methoxypyridin-3-yl) isoquinolin-3-yl)-2-fluoro-cyclopropane-1-carboxamide  48

cis-N-[8-amino-6-(2- hydroxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro- cyclopropane-1-carboxamide  49

cis-N-[8-amino-6-(5-fluoro- 4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclo- propane-1-carboxamide  50

cis-N-[8-amino-6-(3-pyridyl)- 3-isoquinolyl]-2-fluoro-cyclo-propane-1-carboxamide  51

trans-N-[8-amino-6-(3-methyl- 4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropane-1- carboxamide  52, 102

trans-N-[8-amino-7-fluoro-6- (4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano- cyclopropane-1-carboxamide  54, 92,  93

trans-N-(8-amino-6-(5-methyl- 2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)- 2-cyanocyclopropane-1- carboxamide  55

cis-N-(8-amino-6-(2-ethyl-5- oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide  56

trans-N-(8-amino-6-(4- ethylpyridin-3-yl)-2,7- naphthyridin-3-yl)-2-cyanocyclopropane-1- carboxamide  57

trans-N-(8-amino-6-(1,2- dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-cyano- cyclopropane-1-carboxamide  59

cis-N-[8-amino-6-(3-methyl- 4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropane-1- carboxamide  60

trans-N-(8-amino-6-(4-(1,1- difluoroethyl)pyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide  61

N-(8-amino-6-(4-methyl- pyridin-3-yl)isoquinolin-3-yl)-2-(morpholin-3-yl) acetamide  62

trans-N-(8-amino-6-(4- methylisothiazol-5-yl) isoquinolin-3-yl)-2-cyano-cyclopropanee-1- arboxamide  63

trans-N-[8-amino-6-[6- (difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2- cyanocyclopropane-1- carboxamide  65, 94,  95

trans-N-[8-amino-6-[4-(2- hydroxyethyl)-3-pyridyl]-3-isoquinolyl]-2-cyanocyclo- propane-1-carboxamide  66

(1S,2S)-N-(8-amino-6-(4- ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane- 1-carboxamide  67, 71,  72

trans-N-(8-amino-6-(4-ethyl- pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide  68

cis-N-(8-amino-6-(4-ethyl- pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane- 1-carboxamide  69

trans-N-(8-amino-6-(6-cyano- 4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide  70, 107, 123

trans-N-(8-amino-6-(8- methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide  73, 74

trans-N-(8-amino-6-(4- methylpyridin-3-yl) isoquinolin-3-yl)-2-cyano-cyclopropane-1- carboxamide  75, 170

trans-N-(8-amino-6-(1- methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)isoquinolin- 3-yl)-2-cyanocyclopropane- 1-carboxamide  76,171

trans-N-(8-amino-6-(1- methyl-1H-pyrazolo [3,4-c]pyridin-4-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide  77

N-(8-amino-6-(4-ethyl- pyridin-3-yl)isoquinolin- 3-yl)-2-(1H-pyrazol-5-yl)acetamide  78, 109

trans-N-(8-amino-6-(6- methylimidazo[1,2-a] pyridin-7-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide  79, 110

5-(8-amino-3-(trans-2- cyanocyclopropane-1- carboxamido)isoquinolin-6-yl)-N,1-dimethyl-1H- pyrazole-3-carboxamide  80, 113

trans-N-[8-amino-7-cyano- 6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyanocyclo- propane-1-carboxamide  81, 122

trans-N-(8-amino-6-(3- (trifluoromethyl)-1H- pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide  82, 139

trans-N-(8-amino-6-(1H- pyrazol-4-yl)isoquinolin- 3-yl)-2-cyanocyclo-propane-1-carboxamide  85, 119

trans-N-(8-amino-6-(4- methylpyridin-3-yl) isoquinolin-3-yl)-2-(hydroxymethyl)cyclo- propane-1-carboxamide  86, 172

trans-N-(8-amino-6-(2- methyl-2H-pyrazolo [3,4-c]pyridin-4-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide  87, 117

trans-N-(8-amino-6-(1- methyl-4-oxo-1,4- dihydropyridin-2-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide  88, 115

trans-N-(8-amino-7- methyl-6-(4-methyl- pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide  89, 146

trans-N-(8-amino-7- chloro-6-(4-methyl- pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide  90, 116

trans-N-(8-amino-6-(4- (dimethylamino)pyridin- 3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide  91, 157

4-(8-amino-3-(trans-2- cyanocyclopropane-1- carboxamido)isoquinolin-6-yl)-3-methyl-N-(2,2,2- trifluoroethyl)benzamide  98

N-(8-amino-6-(4-methyl- isothiazol-3-yl)isoquinolin- 3-yl)-2-cyanocyclo-propane-1-carboxamide  99, 136

3-(8-amino-3-(trans-2- cyanocyclopropane-1- carboxamido)isoquinolin-6-yl)-N,4-dimethyl- benzamide 100, 173

trans-N-(8-amino-6-(5,5- dimethyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 101, 174

trans-N-(8-amino-6-((S)-4- isopropyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 103, 124

trans-N-(8-amino-6-((R)-4- methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 104

105, 118

trans-N-(8-amino-6-(3- (hydroxymethyl)-5-methyl- 1H-pyrazol-4-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 106, 145

trans-N-(8-amino-5,7- difluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 125

(1S,2S)-N-(8-amino-6-(2- methyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2- fluorocyclopropanecarboxamide 126

trans-N-(8-amino-7-fluoro- 6-((R)-4-methyl-2- oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 127

trans-N-(8-amino-6-((S)- 4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 128

(1S,2S)-N-(8-amino-6- ((S)-4-methyl-2- oxooxazolidin-3-yl)isoquinolin-3-yl)-2- fluorocyclopropane-1- carboxamide 130

trans-N-(8-amino-6-(4- methylisothiazol-3-yl) isoquinolin-1-yl)-2-cyanocyclopropane-1- carboxamide 131

trans-N-(8-amino-6-((R)- 3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 132

trans-N-(8-amino-6-((S)- 3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 133

trans-N-[8-amino-6-(5- isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2- cyano-cyclopropane-1- carboxamide 134

trans-N-[8-amino-6-(2- oxo-1,3-benzoxazol-3-yl)- 3-isoquinolyl]-2-cyano-cyclopropane-1-carboxamide 135

1-[8-amino-7-fluoro-6-(4- methyl-3-pyridyl)-3- isoquinolyl]-3-methylurea138

trans-N-(8-amino-6-(3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide 140

trans-N-(8-amino-6-(2- oxo-2,3-dihydro-1H-benzo [d]imidazol-1-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 143

trans-N-(8-amino-6-(4- methylpyridin-3-yl)-7- (trifluoromethyl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 144

trans-N-(8-amino-6-(5- methyl-2-oxoimidazolidin-1-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 145

trans-N-(8-amino-5,7- difluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 147

1-(8-amino-7-chloro-6-(4- methylpyridin-3-yl)isoquinolin-yl)-3-methylurea 148

1-(8-amino-5-chloro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea 149

1-(8-amino-5-cyano-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea 150

1-(8-amino-7-cyano-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea 151

trans-N-[8-amino-6-(2- oxooxazolidin-5-yl)-3- isoquinolyl]-2-cyano-cyclopropane-1- carboxamide 153

trans-N-[8-amino-7- (hydroxymethyl)-6-(4- methyl-3-pyridyl)-3-isoquinolyl]-2-cyano- cyclopropane-1-carboxamide 154

1-[8-amino-6-(4-methyl- 2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3-isopropylurea 155

N-(8-amino-6-(4-ethyl- pyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl) acetamide 156

trans-N-(8-amino-6-(5- amino-4-methylpyridin-3- yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 159

trans-N-(8-amino-6-(4- methyl-2-oxooxazol- 3(2H)-yl)isoquinolin-3-yl)-2-cyanocyclopropane- 1-carboxamide 160

trans-N-(8-amino-6-(2- methyl-6-oxopiperazin- 1-yl)isoquinolin-3-yl)-2-cyanocyclopropane- 1-carboxamide 161

trans-N-(8-amino-7- fluoro-6-((S)-4-methyl- 2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 162

(1S,2S)-N-(8-amino- 6-(5-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 163

(1R,2R)-N-(8-amino-6- (5-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 164

(1S,2S)-N-(8-amino-6- ((R)-4-methyl-2- oxooxazolidin-3-yl)isoquinolin-3-yl)-2- fluorocyclopropane-1- carboxamide 165

(1S,2R)-N-(8-amino- 6-((R)-4-methyl-2- oxooxazolidin-3-yl)isoquinolin-3-yl)-2- fluorocyclopropane-1- carboxamide 166

(1S,2S)-N-(8-amino- 6-(5-amino-4-methyl- pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide 167

(1R,2R)-N-(8-amino-6- (5-amino-4-methyl- pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide 168, 169

trans-N-(8-amino-6-(4- methylisothiazol-5-yl) isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 175

trans-N-(8-amino-6- ((R)-4-isopropyl-2- oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 176

trans-N-(8-amino-6- (2-oxooxazolidin-3-yl) isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 177

trans-N-(8-amino-6-(2- oxotetrahydro-2H- cyclopenta[d]oxazol-3(3aH)-yl)isoquinolin- 3-yl)-2-cyanocyclo- propane-1-carboxamide 178

trans-N-(8-amino-6- (N,N-dimethylsulfamoyl) isoquinolin-3-yl)cyclopropane-1,2- dicarboxamide 179

trans-N-(8-amino-6-(N,N- dimethylsulfamoyl) isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 180

(1S,2S)-N-(8-amino-6-(4- methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl) isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl) cyclopropane-1-carboxamide 181

(1R,2R)-N-(8-amino-6-(4- methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl) isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl) cyclopropane-1-carboxamide 182

(1R,2R)-N-(8-amino-6-(4- methyl-2-phenylpyridin-3-yl)isoquinolin-3-yl)-2-(1- methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide 183

(1S,2S)-N-(8-amino-6-(4- methyl-2-phenylpyridin-3-yl)isoquinolin-3-yl)-2-(1- methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide 184

trans-N-(8-amino-6-(4- methyl-2-(piperidin-1-yl)pyridin-3-yl)isoquinolin- 3-yl)-2-(1-methyl-1H- pyrazol-4-yl)cyclopropane-1-carboxamide 185

trans-N-(8-amino-6-(2- amino-3-methylpyridin-4-yl)isoquinolin-3-yl)-2-(1- methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide 186

trans-N-(8-amino-6-[4- methyl-5-[(propan-2-yl) amino]pyridin-3-yl]isoquinolin-3-yl)-2- cyanocyclopropane-1- carboxamide 187

trans-N-(8-amino-6-(4- methyl-2-(1-methyl-1H- pyrazol-4-yl)pyridin-3-yl)isoquinolin-3-yl)-2- (cyanomethylcyclo- propane-1-carboxamide 188

N-(8-amino-6-(2,3- dihydro-1H-pyrrolo [2,3-c]pyridin-4-yl)isoquinolin-3-yl)cyclo- propanecarboxamide 189, 190

N-(8-amino-6-(2-methyl- 2,3-dihydro-1H-pyrrolo [2,3-c]pyridin-4-yl)isoquinolin-3-yl)cyclo- propanecarboxamide 191, 192

(1,2)trans-N-(8-amino- 6-(4-methylpyridin-3-yl) isoquinolin-3-yl)-2-(cyanomethyl)-3- methylcyclopropane-1- carboxamide 193, 194

2-(4-(8-amino-7-fluoro- 6-(4-methylpyridin-3-yl) isoquinolin-3-ylamino)-1H-pyrazol-1-yl) propanenitrile 195, 196, 197, 198

(1,3)trans-N-(8-amino-7- fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane- 1-carboxamide 199, 200

2-(3-(8-amino-6-(4- methylpyridin-3-yl) isoquinolin-3-ylamino)-1H-pyrazol-1-yl) propanenitrile 201, 202

2-(4-(8-amino-6-(4- methylpyridin-3-yl) isoquinolin-3-ylamino)-1H-pyrazol-1-yl) propanenitrile 203

2-(4-(8-amino-5-chloro- 6-(4-methylpyridin-3- yl)isoquinolin-3-ylamino)-1H-pyrazol- 1-yl)propanenitrile 204

2-(4-(8-amino-5,7- dichloro-6-(4- methylpyridin-3-yl)isoquinolin-3-ylamino)- 1H-pyrazol-1-yl) propanenitrile 205, 206

2-(4-(8-amino-7-chloro- 6-(4-methylpyridin-3-yl) isoquinolin-3-ylamino)-1H-pyrazol-1-yl) propanenitrile 207, 208

trans-N-(8-amino-6-(4- methyl-2-(pyrrolidin-1- yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1- methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide 209

trans-N-(8-amino-6-(5- amino-4-methylpyridin- 3-yl)-7-chloroisoquinolin-3-yl)-2-(cyanomethyl) cyclopropane-1-carboxamide 210, 211

trans-N-(8-amino-6-(4- methyl-2-(1-methyl-1H- pyrazol-4-yl)pyridin-3-yl)isoquinolin-3-yl)-2- (1-methyl-1H-pyrazol- 4-yl)cyclopropane-1-carboxamide 212, 213, 214, 215

(1,3)trans-N-(8-amino- 6-(4-methylpyridin-3-yl) isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H- pyrazol-4-yl)cyclo- propane-1-carboxamide 216,217

trans-N-(8-amino-6- (2,6-dichlorophenyl) isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol- 4-yl)cyclopropane-1- carboxamide 218, 219

trans-N-(8-amino-6- (2,6-difluorophenyl) isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol- 4-yl)cyclopropane-1- carboxamide 220, 221

trans-N-(8-amino-6- (2-cyano-6-methyl- phenyl)isoquinolin-3-yl)-2-cyanocyclo- propane-1-carboxamide 222, 223

trans-N-(8-amino-6-(4- methyl-2-(1-methyl-1H- pyrazol-3-yl)pyridin-3-yl)isoquinolin-3-yl)-2- (1-methyl-1H-pyrazol- 4-yl)cyclopropane-1-carboxamide 224

(1R,5S,6r)-N-(8-amino- 7-chloro-6-(4-methyl- pyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo [3.1.0]hexane-6- carboxamide 225

(1R,5S,6r)-N-(8-amino- 5-chloro-6-(4-methyl- pyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo [3.1.0]hexane-6- carboxamide 226

(1R,5S,6r)-N-(8-amino- 5,7-dichloro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-3- hydroxybicyclo[3.1.0] hexane-6-carboxamide 227

2-((8-amino-7-fluoro-6- (4-methylpyridin-3-yl) isoquinolin-3-yl)amino)-4,6-dimethyl-5,6- dihydro-4H-pyrazolo [1,5-d][1,4]diazepin- 7(8H)-one228

2′-((8-amino-7-fluoro- 6-(4-methylpyridin-3- yl)isoquinolin-3-yl)amino)-6′-methyl-5′,6′- dihydrospiro[cyclo- propane-1,4′-pyrazolo[1,5-d][1,4]diazepin]- 7′(8′H)-one 229

2-((8-amino-6-(5- amino-4-methylpyridin- 3-yl)-7-fluoroiso-quinolin-3-yl)amino)- 6-methyl-5,6-dihydro- 4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 230

2-((8-amino-7-fluoro- 6-(4-methylpyridin-3- yl)isoquinolin-3-yl)amino)-6-methyl-5,6- dihydro-4H-pyrazolo [1,5-d][1,4]diazepin- 7(8H)-one 9, 10,  11, 12

 

(1,3)trans-N-(8- amino-7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] oxazin-7-yl)isoquinolin- 3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4- yl)cyclopropane-1- carboxamide  29

1-(8-amino-7-fluoro-6- (8-methyl-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin- 3-yl)-3-(cyclopropyl- methyl)urea  33, 34,  35,36

 

(1,3)trans-N-(8-amino- 7-fluoro-6-(8-methyl- 2,3-dihydro-1H-pyrido[2,3-b][1,4] oxazin-7-yl)isoquinolin- 3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)cyclopropane-1- carboxamide  53

tetrahydro-2H-pyran-4- yl (8-amino-6-(5-amino- 4-methylpyridin-3-yl)-7-fluoroisoquinolin-3- yl)carbamate  58

2-methoxyethyl (8- amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl) carbamate  64

N-(8-amino-6-(5-amino- 4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)cyclopropanecarboxamide  83, 84

trans-N-(8-amino-6-(5- amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3- yl)-2-cyanocyclopropane- 1-carboxamide  96

7-fluoro-6-(8-methyl-2,3- dihydro-1H-pyrido[2,3-b] [1,4]oxazin-7-yl)isoquinoline-3,8-diamine  97

3,8-diamino-6-(4-methyl- pyridin-3-yl)isoquinoline- 7-carbonitrile 111,112

1-(8-amino-7-fluoro-6- (8-methyl-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin- 3-yl)-3-(1-(1-methyl- 1H-pyrazol-4-yl)ethyl)urea 114

cyclopropylmethyl (8- amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl) carbamate 120, 121

trans-N-(8-amino-6-(5- amino-4-methylpyridin- 3-yl)-7-fluoroiso-quinolin-3-yl)-2,2- dimethyl-3-(1-methyl- 1H-pyrazol-4-yl)cyclo-propane-1-carboxamide 129

isopropyl (8-amino-6- (5-amino-4-methyl- pyridin-3-yl)-7-fluoroiso-quinolin-3-yl)carbamate 137

1-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl) isoquinolin-3-yl)-3-(1-cyanopropan-2-yl)urea 141

7-fluoro-6-(4-methyl- pyridin-3-yl)-N3-(3- (morpholin-3-yl)phenyl)isoquinoline-3,8-diamine 142

(S)-7-fluoro-6-(4- methylpyridin-3-yl)-N3- (3-(morpholin-3-yl)phenyl)isoquinoline- 3,8-diamine 152

cis-N-(8-amino-6-(2,6- dichlorophenyl)-7- fluoroisoquinolin-3-yl)-2-fluorocyclopropane- 1-carboxamide 158

(1R,5S,6r)-N-(8-amino- 6-(5-amino-4-methyl- pyridin-3-yl)-7-fluoro-isoquinolin-3-yl)-3- oxabicyclo[3.1.0]hexane- 6-carboxamide

TABLE 2 Compound No. Structure Name 231

2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(methyl-d3)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 232

2-((6-(1-acetyl-1,2,3,6- tetrahydropyridin-4-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6- isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 233

2-((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)amino)-6-isopropyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 234

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,5-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 235

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,5,6-trimethyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 236,

(1,2)trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin- 3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide 237,

238,

239

240

2-((8-amino-7-fluoro-6-((2-oxo-1,2-dihydropyridin-3-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 241

N-(8-amino-3-((6-isopropyl-7-oxo- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin- 6-yl)ethanesulfonamide 242

5-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin- 6-yl)-4-ethyloxazol-2(3H)-one243

2-((8-amino-6-(5-amino-4- chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 244

2-((8-amino-7-fluoro-6-((4-methyl-2-oxopiperazin-1-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 245

5-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-N,N,4-trimethylpyrimidine-2- carboxamide 246

2-((8-amino-6-(5-amino-4- methoxypyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6- isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 247

6-(5-amino-4-methylpyridin-3-yl)-N3- (5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7- fluoroisoquinoline-3,8-diamine248

2-((8-amino-7-fluoro-6-(2-methylprop-1-en-1-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 249

2-((6-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 250

2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-7-methyl-6,7-dihydro-5H- imidazo[1,2-d][1,4]diazepin-8(9H)-one251

2-((8-amino-6-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 252

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,5-dihydro-7H- pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide 253

2-((8-amino-6-cyclopropyl-7- fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 254

2-((8-amino-7-fluoroisoquinolin-3- yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 255

2-((8-amino-7-fluoro-6-(2-isopropoxy-4-methylpyrimidin-5-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 256

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-isopropyl-4,5-dihydro-7H-pyrazolo[5,1-d][1,2,5]thiadiazine 6,6-dioxide 257

2-((8-amino-6-(benzyloxy)-7- fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 258

2-((8-amino-7-fluoro-6- methylisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 259

2-((8-amino-7-fluoro-6- methoxyisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 260

2-((8-amino-7-fluoro-6-((pyridin-2-yloxy)methyl)isoquinolin-3-yl)amino)- 6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 261

2-((8-amino-7-fluoro-6-((2-oxopyridin- 1(2H)-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 262

(±)-6-(5-amino-4-methylpyridin-3-yl)- N3-(7,7-difluoro-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)-7-fluoroisoquinoline-3,8-diamine 263

5-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-1-methyl-1,3- dihydroisothiazolo[4,3-b]pyridine 2,2- dioxide264

2-(8-amino-3-((6-methyl-7-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin- 6-yl)cyclopropane-1-carbonitrile265

6-(5-amino-4-methylpyridin-3-yl)-7- fluoro-N3-((4S,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine 266

6-(5-amino-4-methylpyridin-3-yl)-7- fluoro-N3-((4R,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Stereochemistry arbitrarily assigned) 267

6-(5-amino-4-methylpyridin-3-yl)-7- fluoro-N3-((4S,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Stereochemistry arbitrarily assigned) 268

6-(5-amino-4-methylpyridin-3-yl)-7- fluoro-N3-((4R,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Stereochemistry arbitrarily assigned) 269

5-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-1-ethyl-1H-pyrazole-3-carbonitrile 270

2-((8-amino-7-fluoro-6-(5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)amino)-6-isopropyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 271

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H,8H- pyrazolo[1,5-c][1,3]thiazepine 7,7-dioxide 272

2-((8-amino-7-fluoro-6-(5-methyl-2- oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 273

.2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(2-hydroxy-2- methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 274

(R)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 275

(S)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistry arbitrarilyassigned) 276

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-methyl-4,5-dihydro-7H- pyrazolo[5,1-d][1,2,5]thiadiazine6,6- dioxide 277

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(oxetan-3-ylmethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 278

2-((8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 279,

(1,3)trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4- yl)cyclopropane-1-carboxamide280,

281,

282

283

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-cyclopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 284

2-((8-amino-6-(3,4-dihydro-2H- pyrido[4,3-b][1,4]oxazin-8-yl)-7-fluoroisoquinolin-3-yl)amino)-6- isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 285

3-(8-amino-3-((6-methyl-7-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin- 6-yl)-4-methyloxazolidin-2-one286

2-((8-amino-6-(5-amino-4-ethylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 287

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-ethyl-4H,6H- pyrazolo[1,5-c]thiazole 5,5-dioxide 288

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(cyclopropylmethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 289

2-((8-amino-7-fluoro-6-(5-hydroxy-4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 290

2-((8-amino-7-fluoro-6-(5- (hydroxymethyl)-4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-isopropyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 291

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2-methoxyethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 292

2-((8-amino-7-fluoro-6-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)amino)-6-methyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 293

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro- 4H,8H-pyrazolo[5,1-c][1,2,6]thiadiazepine 7,7-dioxide 294,

(1,3)trans-N-(8-amino-6-(5-amino-6- methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane- 1-carboxamide 295,

296,

297

298

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-ethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 299

2-((8-amino-6-(5-amino-4,6- dimethylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 300

2-((8-amino-6-(2-amino-3- methylpyridin-4-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 301

2-((8-amino-7-fluoro-6-(5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 302

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-methyl-4,5- dihydropyrazolo[1,5-a]pyrazin-6(7H)- one 303

(E)-2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-4-((1-methyl-1H- pyrazol-4-yl)methylene)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 304

2-((8-amino-6-(3,5-dimethyl-1H- pyrazol-4-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 305

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2,2-trifluoroethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 306

2-((8-amino-6-(5-amino-4- chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 307

2-((8-amino-7-fluoro-6-(5-methyl-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)isoquinolin-3-yl)amino)-6-methyl- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 308

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-fluoro-6-methyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 309

(R)-2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-fluoro-6-methyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistry arbitrarilyassigned) 310

(S)-2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-fluoro-6-methyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistry arbitrarilyassigned) 311

2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-4-hydroxy-4,6-dimethyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 312

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 313

2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-4-hydroxy-4- (methoxymethyl)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 314

2′-((8-amino-7-fluoro-6-(1,3,5-trimethyl- 1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-6′-methyl-5′,6′- dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)- one 315

2-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one 316

2′-((8-amino-6-(5-amino-4- methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6′-methyl-5′,6′- dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)- one 317

2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-4-methylene-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 318

2-((8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 319,

(1,2)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- (1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide 320,

321,

322

323,

N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-(1H-imidazol-4- yl)cyclopropane-1-carboxamide 324

325

cis-N-(8-amino-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1- carboxamide 326

(1S,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- (hydroxymethyl)cyclopropane-1-carboxamide (Hydroxymethyl trans to amide; Absolute stereochemistryarbitrarily assigned) 327

(1R,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- (hydroxymethyl)cyclopropane-1-carboxamide (Hydroxymethyl trans to amide; Absolute stereochemistryarbitrarily assigned) 328

N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)cyclopropane-1- carboxamide329,

(1,3)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide 330,

331,

332

333

trans-N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1- carboxamide 334

(1R,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1- carboxamide 335

(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1- carboxamide 336

N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-azabicyclo[2.1.1]hexane-2-carboxamide 337,

(1,2)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide 338,

339,

340

341,

cis-N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-((dimethylamino)methyl)cyclopropane- 1-carboxamide 342

343,

N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3- ((dimethylamino)methyl)cyclopropane- 1-carboxamide 344,

345

346,

(1,3)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H- pyrazol-4-yl)cyclopropane-1-carboxamide 347,

348,

349

350,

(1,3)trans-N-(8-amino-7-fluoro-6-(4- methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1- methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide 351,

352,

353

354

N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4- yl)cyclopropane-1-carboxamide 355

(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- (1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide (Relative stereochemistry as drawn;Absolute stereochemistry arbitrarily assigned) 356

(1R,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- (1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide (Relative stereochemistry as drawn;Absolute stereochemistry arbitrarily assigned) 357,

(1,3)trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol- 4-yl)cyclopropane-1-carboxamide358,

359,

360

361

(S)-2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistryarbitrarily assigned) 362

(R)-2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistryarbitrarily assigned) 363,

trans-N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)cyclopropane-1- carboxamide 364

365,

(1,2)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3- methylcyclopropane-1-carboxamide366,

367,

368

369,

(1,3)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-4-yl)-3-(1-methyl-1H- pyrazol-4-yl)cyclopropane-1-carboxamide 370

371,

exo-N-(8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7- carboxamide 372,

373,

374

375,

(1,3)trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-imidazol- 5-yl)cyclopropane-1-carboxamide376,

377,

378

379,

(1,2)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)- 1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide 380,

381,

382

383,

(1,2)trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1- carboxamide 384,

385,

386

387

2-((8-amino-7-fluoro-6-(4- methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(2,2,2-trifluoroethyl)-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 388

2-((8-amino-6-(3-amino-2- methylphenyl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 389

6-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-5-methylbenzo[d]oxazol-2(3H)- one 390

2-((8-amino-6-(3-amino-2- methylphenyl)-7-fluoroisoquinolin-3-yl)amino)-4-hydroxy-6-methyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

TABLE 3 Compound No. Structure Name 391

cis-2-(2-acetamidoethyl)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide

392

cis-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide

393

cis-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)-2-(2-hydroxyethyl)cyclopropane-1-carboxamide

394

3-methyltetrahydrofuran-3-yl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)carbamate 395

3-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate 396

3-methyloxetan-3-yl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3- yl)carbamate 397

3-methyloxetan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate 398

1,1-dioxidotetrahydrothiophen-3-yl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)carbamate 399

1,1-dioxidotetrahydrothiophen-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate 400

1,3-dimethyl-5-oxopyrrolidin-3-yl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)carbamate 401

1,3-dimethyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate 402

1-acetyl-3-methylazetidin-3-yl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)carbamate 403

1-acetyl-3-methylazetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate 404

1-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-3-methylurea 405

1-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin- 3-yl)-3-methylurea 406

2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-4H,6H-pyrazolo[1,5-e][1,2,5]oxadiazepin- 7(8H)-one 407

2-((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)amino)-6-methyl-4H,6H-pyrazolo[1,5- e][1,2,5]oxadiazepin-7(8H)-one408

2′-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6′-methyl-6′H-spiro[cyclopropane-1,4′-pyrazolo[1,5- e][1,2,5]oxadiazepin]-7′(8′H)-one409

2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,4,6- trimethyl-4H,6H-pyrazolo[1,5-e][1,2,5]oxadiazepin-7(8H)-one 410

(+/−)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,6- dimethyl-4H,6H-pyrazolo[1,5-e][1,2,5]oxadiazepin-7(8H)-one 411

(+/−)-2-((8-amino-7-fluoro-6-(4-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 412

(+/−)-2-((8-amino-7-fluoro-6-(4-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 413

(+/−)-6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol 414

2-((8-amino-7-fluoro-6-(5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 415

N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoro-6-(5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinoline-3,8-diamine 416

2-((8-amino-7-fluoro-6-(5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 417

(+/−)-2-((8-amino-7-fluoro-6-(4-fluoro-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 418

(+/−)-2-((8-amino-7-fluoro-6-(4-fluoro-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 419

(+/−)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoro-6-(4-fluoro-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinoline-3,8- diamine 420

2-((8-amino-7-fluoro-6-(4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 421

2-((8-amino-7-fluoro-6-(4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 422

N3-(5,6-dihydro-11H-imidazo[1,2-alpyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoro-6-(4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinoline-3,8-diamine 423

2-((8-amino-7-fluoro-6-(4-methyl-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 424

8-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4,9-dimethyl-1,2,3,4-tetrahydro-5H-pyrido[3,2- e][1,4]diazepin-5-one 425

8-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4,9-dimethyl-1,2,3,4-tetrahydro-5H-pyrido[3,2- e][1,4]diazepin-5-one 426

8-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4,9-dimethyl-1,2,3,4-tetrahydro-5H-pyrido[3,2-e][1,4]diazepin-5-one 427

2-((8-amino-6-(8,8-difluoro-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 428

2-((8-amino-6-(8,8-difluoro-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 429

6-(8,8-difluoro-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8-diamine 430

(+/−)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoro-6-(8-fluoro-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinoline-3,8-diamine 431

(+/−)-2-((8-amino-7-fluoro-6-(8-fluoro-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 432

(+/−)-2-((8-amino-7-fluoro-6-(8-fluoro-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 433

7-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-3,8-dimethyl-2,3-dihydropyrido[3,2- d]pyrimidin-4(1H)-one 434

7-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-3,8-dimethyl-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one 435

7-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-3,8-dimethyl-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one 436

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 437

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 438

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 439

(+/−)-6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-ol 440

(+/−)-7-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-ol 441

(+/−)-2-((8-amino-7-fluoro-6-(8-hydroxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 442

(+/−)-2-((8-amino-7-fluoro-6-(8-hydroxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 443

(+/−)-7-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-4- carbonitrile 444

(+/−)-7-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-4- carbonitrile 445

(+/−)-7-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-4-carbonitrile 446

3-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4- methylpyridine 1-oxide447

3-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridine 1- oxide 448

3-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridine 1- oxide 449

N-(5-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)methanesulfonamide 450

N-(5-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3- yl)methanesulfonamide 451

N-(5-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)methanesulfonamide 452

N-(5-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)methanesulfinamide 453

N-(5-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)methanesulfinamide 454

N-(5-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3- yl)methanesulfinamide 455

2-((8-amino-7-fluoro-6-(7-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 456

2-((8-amino-7-fluoro-6-(7-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 457

6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-7-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one 458

2-((8-amino-6-(2,7-dimethyl-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-b]pyridin-6-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 459

2-((8-amino-6-(2,7-dimethyl-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-b]pyridin-6-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 460

6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-2,7-dimethyl-1,2-dihydro-3H-pyrazolo[4,3-b]pyridin-3-one 461

2-((8-amino-7-fluoro-6-(7-methyl-2,2-dioxido-1,3-dihydroisothiazolo[4,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 462

2-((8-amino-7-fluoro-6-(7-methyl-2,2-dioxido-1,3-dihydroisothiazolo[4,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 463

6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-7-methyl-1,3- dihydroisothiazolo[4,3-b]pyridine2,2-dioxide 464

2-((8-amino-7-fluoro-6-(7-methyl-2-oxido-1,3-dihydroisothiazolo[4,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 465

2-((8-amino-7-fluoro-6-(7-methyl-2-oxido-1,3-dihydroisothiazolo[4,3-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 466

6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-7-methyl-1,3- dihydroisothiazolo[4,3-b]pyridine2-oxide 467

(+/−)-6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-2,2,7-trimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-3-ol 468

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-2,2,7-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 469

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-2,2,7-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 470

(+/−)-6-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-3-hydroxy-3,7-dimethyl-1,3-dihydro-2H-pyrrolo[3,2- b]pyridin-2-one 471

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 472

(+/−)-2-((8-amino-7-fluoro-6-(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 473

2-((8-amino-6-(4,6-dimethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 474

3-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4,6-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 475

2-((8-amino-6-(4,6-dimethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 476

8-amino-7-fluoro-N-methyl-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-N-(6-oxo-1,6-dihydropyridin-2-yl)isoquinoline-6- carboxamide 477

8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoro-N-methyl-N-(6-oxo-1,6-dihydropyridin-2-yl)isoquinoline-6-carboxamide 478

8-amino-7-fluoro-N-methyl-N-(6-oxo-1,6-dihydropyridin-2-yl)-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinoline-6-carboxamide 479

8-amino-7-fluoro-N-methyl-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-N-(6-oxo-1,6-dihydropyrazin-2-yl)isoquinoline-6- carboxamide 480

8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoro-N-methyl-N-(6-oxo-1,6-dihydropyrazin-2-yl)isoquinoline-6-carboxamide 481

8-amino-7-fluoro-N-methyl-N-(6-oxo-1,6-dihydropyrazin-2-yl)-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinoline-6-carboxamide 482

2-((8-amino-6-(difluoromethyl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 483

2-((8-amino-6-(difluoromethyl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 484

6-(difluoromethyl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8-diamine 485

(+/−)-2-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d]1,4]diazepin-2-yl)amino)isoquinolin-6- yl)propanenitrile 486

(+/−)-2-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6- yl)propanenitrile 487

(+/−)-2-(8-amino-7-fluoro-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)propanenitrile 488

(+/−)-2-((8-amino-6-(3-amino-9-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-8-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 489

(+/−)-6-(3-amino-9-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-8-yl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8- diamine 490

2-((8-amino-7-fluoro-6-(9-methyl-3,3-dioxido-1,2-dihydro)-4H-pyrido[3,2- f][1,3,5]oxathiazepin-8-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 491

2-((8-amino-7-fluoro-6-(9-methyl-3,3-dioxido-1,2-dihydro)-4H-pyrido[3,2- f][1,3,5]oxathiazepin-8-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 492

8-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-9-methyl-1,2-dihydro-4H-pyrido[3,2-f][1,3,5]oxathiazepine 3,3- dioxide 493

2-((8-amino-7-fluoro-6-(4-methyl-5-(1H-pyrazol-1-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 494

2-((8-amino-7-fluoro-6-(4-methyl-5-(1H-pyrazol-1-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 495

2-((6-(5-(1H-imidazol-1-yl)-4-methylpyridin-3-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 496

2-((6-(5-(1H-imidazol-1-yl)-4-methylpyridin-3-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 497

2-((8-amino-7-fluoro-6-(4-methyl-5-(1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 498

2-((8-amino-7-fluoro-6-(4-methyl-5-(1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 499

2-((6-(5-(1H-imidazol-5-yl)-4-methylpyridin-3-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 500

2-((6-(5-(1H-imidazol-5-yl)-4-methylpyridin-3-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 501

(+/−)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(1-methoxypropan-2-yl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 502

(+/−)-2-((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)amino)-6-(1-methoxypropan-2-yl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 503

(+/−)-2-((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)amino)-6-(tetrahydrofuran-3-yl)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 504

(+/−)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(tetrahydrofuran-3-yl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 505

4-(8-amino-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-3-fluoro-5- methylbenzamide 506

4-(8-amino-3-((7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2- yl)amino)isoquinolin-6-yl)-3-fluoro-5-methylbenzamide 507

1-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-5,6-dimethylpyrimidin- 4(1H)-one 508

2-((8-amino-6-(5,6-dimethyl-4-oxopyrimidin-1(4H)-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 509

2-((8-amino-6-(5,6-dimethyl-4-oxopyrimidin-1(4H)-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 510

1-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-6-(hydroxymethyl)-6- methylpyrimidin-4(1H)-one511

2-((8-amino-7-fluoro-6-(5-(hydroxymethyl)-6-methyl-4-oxopyrimidin-1(4H)-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 512

2-((8-amino-7-fluoro-6-(5-(hydroxymethyl)-6-methyl-4-oxopyrimidin-1(4H)-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 513

5-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-1,6-dimethylpyrimidin- 2(1H)-one 514

2-((8-amino-6-(1,6-dimethyl-2-oxo-1,2-dihydropyrimidin-5-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 515

2-((8-amino-6-(1,6-dimethyl-2-oxo-1,2-dihydropyrimidin-5-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 516

5-amino-1-(8-amino-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-6- methylpyrimidin-4(1H)-one 517

2-((8-amino-6-(5-amino-6-methyl-4-oxopyrimidin-1(4H)-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 518

2-((8-amino-6-(5-amino-6-methyl-4-oxopyrimidin-1(4H)-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 519

(1R,6S)-3-acetamido-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3-yl)bicyclo[4.1.0]heptane-7-carboxamide(1R,3R,6S,7S)-3-acetamido-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)bicyclo[4.1.0]heptane-7-carboxamide

520

8-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-3-methyl-2,3-dihydropyrazolo[5,1-b][1,3,6]thiadiazepin- 4(5H)-one 1,1-dioxide 521

7-fluoro-N³-(1-methyl-1,4,9,10-tetrahydroimidazo[4,5-e]pyrazolo[1,5-a]azepin-7-yl)-6-(4-methylpyridin-3-yl)isoquinoline-3,8- diamine 522

2′-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one 523

2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-3-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 524

2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-3,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one 525

2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-3-hydroxy-6-methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one 526

(4S,8R)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6- methyl-5,6-dihydro-4H-4,8-ethanopyrazolo[1,5-d][1,4]diazepin-7(8H)-one 527

2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6,7,8-tetrahydroimidazo[4,5-b]azepin-5(1H)-one 5282-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[1,5-a]azepin-7(8H)-one

In some embodiments, the compound is selected from the group consistingof Compound Nos. 1-230 in Table 1, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the groupconsisting of Compound Nos. 1, 2, 3, 4, 5, 6, 7, 8, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 59, 60,61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 113, 115, 116, 117,118, 119, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134,135, 136, 138, 139, 140, 143, 144, 145, 146, 147, 148, 149, 150, 151,153, 154, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167,168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181,182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195,196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209,210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223,224, 225, 226, 227, 228, 229 and 230, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound is selected from thegroup consisting of Compound Nos. 9-12, 29, 33-36, 53, 58, 64, 83, 84,96, 97, 111, 112, 114, 120, 121, 129, 137, 141, 142, 152 and 158, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group consisting of Compound Nos. 231-390in Table 2, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound is selected from the group consisting ofCompound Nos. 391-528 in Table 3, or a pharmaceutically acceptable saltthereof.

Compounds of Formula I or Ia described herein or a salt thereof mayexist in stereoisomeric forms (e.g., it contains one or more asymmetriccarbon atoms). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe subject matter disclosed herein. Likewise, it is understood that acompound or salt of Formulas I or Ia may exist in tautomeric forms otherthan that shown in the formula and these are also included within thescope of the subject matter disclosed herein. It is to be understoodthat the subject matter disclosed herein includes combinations andsubsets of the particular groups described herein. The scope of thesubject matter disclosed herein includes mixtures of stereoisomers aswell as purified enantiomers or enantiomerically/diastereomericallyenriched mixtures. It is to be understood that the subject matterdisclosed herein includes combinations and subsets of the particulargroups defined herein.

The subject matter disclosed herein also includes isotopically-labelledforms of the compounds described herein, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds describedherein and pharmaceutically acceptable salts thereof include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine,iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶O, ¹²³I and ¹²⁵I.

The subject matter disclosed herein includes prodrugs, metabolites,derivatives, and pharmaceutically acceptable salts of compounds ofFormula I or Ia. Metabolites of the compounds of Formula I or Ia includecompounds produced by a process comprising contacting a compound ofFormula I or Ia with a mammal for a period of time sufficient to yield ametabolic product thereof.

If the compound of Formula I or Ia is a base, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, methanesulfonic acid, phosphoric acid and the like,or with an organic acid, such as acetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalicacid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,or the like.

If the compound of Formula I or Ia is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

A compound of Formula I or Ia can be in the form of a “prodrug,” whichincludes compounds with moieties which can be metabolized in vivo.Generally, the prodrugs are metabolized in vivo by esterases or by othermechanisms to active drugs. Examples of prodrugs and their uses are wellknown in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”,J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during thefinal isolation and purification of the compounds, or by separatelyreacting the purified compound in its free acid form or hydroxyl with asuitable esterifying agent. Hydroxyl groups can be converted into estersvia treatment with a carboxylic acid. Examples of prodrug moietiesinclude substituted and unsubstituted, branch or unbranched lower alkylester moieties, (e.g., propionoic acid esters), lower alkenyl esters,di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethylester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester),acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters(phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester),substituted (e.g., with methyl, halo, or methoxy substituents) aryl andaryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkylamides, and hydroxy amides. Prodrugs which are converted to active formsthrough other mechanisms in vivo are also included. In aspects, thecompounds of the invention are prodrugs of any of the formulae herein.

General Synthetic Schemes

Compounds of Formula I or Ia can be prepared by precedures in theExamples and generally by Schemes 1 and 2, where R groups are asdescribed in Formula I or Ia, or precursors thereof.

Scheme 1 shows a general synthetic method for preparing a compound ofFormula I or Ia wherein R₂ is A-C(O)—. Reaction of compound A with anactivated acyl compound A-C(O)—X′ results in acylation of the 3-aminogroup giving compound B. Pd-catalysed coupling of compound B with aboronic ester R₂—B(OR)₂ gives compound C. Pd-catalysed coupling ofcompound C with a protected amine gives compound D. Deprotection ofcompound D yields the product of Formula (I-A), where A, R₁ andand R₂are as defined for Formula I or Ia.

Provided is a method for making a compound of Formula (I-A) comprisingreacting a compound C with a protected amine (e.g., HN═C(Ph)₂ orBoc-NH₂) to form compound D, and subjecting compound D to a conditionfor amine deprotection to form compound (I-A), where A, R₁ andand R₂ areas defined for Formula I or Ia. The method may further compriseacylating a compound A (comprising reacting compound A with A-C(O)—X,where X is halogen such as Br or I) to form compound B; reactingcompound B with with a boronic ester R₂—B(OR)₂ (where R is an alkyl oraryl, or the two OR groups together with the boron atom to form a ring)and a Pd catalyst to form a compound C.

Scheme 2 shows a general synthetic method for preparing a compound ofFormula I or Ia wherein R₂ is D. Pd-catalysed coupling of compound Awith a boronic ester R—B(OR)₂, or a pretected amine when the desired R₂group is an amino group, gives compound E. Pd-catalysed coupling ofcompound E with a compound D-X gives compound F. Pd-catalysed couplingof compound C with a protected amine gives compound G. Deprotection ofcompound G yields the product of Formula (I-D), where D, R₁ and R₂ areas defined for Formula I or Ia.

Provided is a method for making a compound of Formula (I-D) comprisingreacting a compound F with a protected amine (e.g., HN═C(Ph)₂ orBoc-NH₂) to form compound D, and subjecting compound D to a conditionfor amine deprotection to form compound (I-A), where A, R₁ andand R₂ areas defined for Formula I or Ia. The method may further comprise reactingcompound A with a boronic ester R₂—B(OR)₂ (where R is an alkyl or aryl,or the two OR groups together with the boron atom to form a ring) and aPd catalyst to form a compound E; and reacting a compound E with acompound D-X (where X is a leaving group such as Cl, Br or I) and a Pdcatalyst to form a compound F. Where the desired R₂ is an optionallysubstituted amino group, the method may further comprise reactingcompound A with a protected amine (e.g., HNRR′ where R and R's are amineprotecting groups) and a Pd catalyst to form a compound E; and reactinga compound E with a compound D-X (where X is a leaving group such as Cl,Br or I) and a Pd catalyst to form a compound F.

Compositions

The presently disclosed compounds can be formulated into pharmaceuticalcompositions along with a pharmaceutically acceptable carrier.

Compounds of Formula I or Ia can be formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.According to this aspect, there is provided a pharmaceutical compositioncomprising a compound of Formula I or Ia in association with apharmaceutically acceptable diluent or carrier.

A typical formulation is prepared by mixing a Formula I or Ia compoundand a carrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and includematerials such as carbohydrates, waxes, water soluble and/or swellablepolymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents,water and the like. The particular carrier, diluent or excipient usedwill depend upon the means and purpose for which the compound of FormulaI or Ia is being applied. Solvents are generally selected based onsolvents recognized by persons skilled in the art as safe (GRAS) to beadministered to a mammal. In general, safe solvents are non-toxicaqueous solvents such as water and other non-toxic solvents that aresoluble or miscible in water. Suitable aqueous solvents include water,ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG300), etc. and mixtures thereof. The formulations may also include oneor more buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents and other known additivesto provide an elegant presentation of the drug (i.e., a compound ofFormula I or Ia or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof Formula I or Ia or stabilized form of the Formula I or Ia compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound ofFormula I or Ia is typically formulated into pharmaceutical dosage formsto provide an easily controllable dosage of the drug and to enablepatient compliance with the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations may be prepared for various routes and typesof administration. For example, a compound of Formula I or Ia having thedesired degree of purity may optionally be mixed with pharmaceuticallyacceptable diluents, carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the formof a lyophilized formulation, milled powder, or an aqueous solution.Formulation may be conducted by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed. The pH of theformulation depends mainly on the particular use and the concentrationof compound, but may range from about 3 to about 8. Formulation in anacetate buffer at pH 5 is a suitable embodiment.

The compounds of Formula I or Ia can be sterile. In particular,formulations to be used for in vivo administration should be sterile.Such sterilization is readily accomplished by filtration through sterilefiltration membranes.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions comprising a compound of Formula I or Iacan be formulated, dosed and administered in a fashion, i.e., amounts,concentrations, schedules, course, vehicles and route of administration,consistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The “therapeutically effective amount”of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to prevent,ameliorate, or treat the coagulation factor mediated disorder. In someembodiments, the amount is below the amount that is toxic to the host orrenders the host more susceptible to bleeding.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16^(th) edition, Osol, A. Ed.(1980).

Sustained-release preparations of Formula I or Ia compounds may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I or Ia, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I or Ia suitable for oraladministration may be prepared as discrete units such as pills,capsules, cachets or tablets each containing a predetermined amount of acompound of Formula I or Ia.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I or Ia intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientsmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients may be formulated in a creamwith an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400), and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions may be constituted from knowningredients in a known manner. While the phase may comprise solely anemulsifier, it may also comprise a mixture of at least one emulsifierand a fat or oil, or both a fat and an oil. A hydrophilic emulsifierincluded together with a lipophilic emulsifier may act as a stabilizer.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations. Emulsifiers and emulsionstabilizers suitable for use in the formulation include Tween® 60, Span®80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerylmono-stearate and sodium lauryl sulfate.

Aqueous suspensions of Formula I or Ia compounds contain the activematerials in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients include a suspending agent, such assodium carboxymethylcellulose, croscarmellose, povidone,methylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

The pharmaceutical compositions of compounds of Formula I or Ia may bein the form of a sterile injectable preparation, such as a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such 1,3-butanediol. The sterile injectable preparation mayalso be prepared as a lyophilized powder. Among the acceptable vehiclesand solvents that may be employed are water, Ringer's solution andisotonic sodium chloride solution. In addition, sterile fixed oils mayconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid may likewisebe used in the preparation of injectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The subject matter further provides veterinary compositions comprisingat least one active ingredient as above defined together with aveterinary carrier therefore. Veterinary carriers are materials usefulfor the purpose of administering the composition and may be solid,liquid or gaseous materials which are otherwise inert or acceptable inthe veterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

In particular embodiments the pharmaceutical composition comprising thepresently disclosed compounds further comprise a chemotherapeutic agent.In some of these embodiments, the chemotherapeutic agent is animmunotherapeutic agent.

Methods

The presently disclosed compounds find use in inhibiting the activity ofthe enzyme HPK1. HPK1, also referred to as mitogen activated proteinkinase kinase kinase kinase 1 or MAP4K1, is a member of the germinalcenter kinase subfamily of Ste20-related serine/threnonine kinases. HPK1functions as a MAP4K by phosphorylating and activating MAP3K proteins,including MEKK1, MLK3 and TAK1, leading to the activation of the MAPKJnk.

In an embodiment, the subject matter disclosed herein is directed to amethod of inhibiting HPK1, the method comprising contacting HPK1 with aneffective amount of a compound of Formula I or Ia or a pharmaceuticalcomposition described herein.

In an embodiment, the subject matter disclosed herein is directed to amethod for enhancing an immune response in a subject in need thereof,wherein the method comprises administering to said subject an effectiveamount of a compound of Formula I or Ia or a pharmaceutical compositiondescribed herein. In certain aspects of this embodiment, the T cells inthe subject have at least one of enhanced priming, enhanced activation,enhanced migration, enhanced proliferation, enhanced survival, andenhanced cytolytic activity relative to prior to the administration ofthe compound or pharmaceutical composition. In certain aspects of thisembodiment, the T cell activation is characterized by an elevatedfrequency of γ-IFN+CD8 T cells or enhanced levels of IL-2 or granzyme Bproduction by T cells relative to prior to administration of thecompound or pharmaceutical composition. In certain aspects of thisembodiment, the number of T cells is elevated relative to prior toadministration of the compound or pharmaceutical composition. In certainaspects of this embodiment, the T cell is an antigen-specific CD8 Tcell. In certain aspects of this embodiment, the antigen presentingcells in the subject have enhanced maturation and activation relativeprior to the administration of the compound or pharmaceuticalcomposition. In certain aspects of this embodiment, the antigenpresenting cells are dendritic cells. In certain aspects of thisembodiment, the maturation of the antigen presenting cells ischaracterized by increased frequency of CD83+ dendritic cells. Incertain aspects of this embodiment, the activation of the antigenpresenting cells is characterized by elevated expression of CD80 andCD86 on dendritic cells.

In the methods described herein, a compound of Formula I or Ia or apharmaceutical composition thereof is administered to a subject that hascancer as described elsewhere herein.

In an embodiment, the subject matter disclosed herein is directed to amethod for treating a HPK1-dependent disorder, the method comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I or Ia or a pharmaceutical composition describedherein. In certain aspects of this embodiment, the HPK1-dependentdisorder is a cancer. In certain aspects of this embodiment, the cancercomprises at least one cancer selected from the group consisting ofcolorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer,breast cancer, pancreatic cancer, a hematological malignancy, and arenal cell carcinoma. In certain aspects of this embodiment, the cancerhas elevated levels of T-cell infiltration. In certain aspects of thisembodiment, the cancer cells in the subject selectively have elevatedexpression of MHC class I antigen expression relative to prior to theadministration of the compound or composition.

In the methods described herein, the method can further compriseadministering a chemotherapeutic agent to said subject. In certainaspects of this embodiment, the chemotherapeutic agent is administeredto the subject simultaneously with the compound or the composition. Incertain aspects of this embodiment, the chemotherapeutic agent isadministered to the subject prior to administration of the compound orthe composition. In certain aspects of this embodiment, thechemotherapeutic agent is administered to the subject afteradministration of the compound or said composition.

HPK1 polynucleotides and polypeptides are known in the art (Hu et al.(1996) Genes Dev. 10: 2251-2264, which is herein incorporated byreference in its entirety). Non-limiting examples of HPK1polynucleotides and polypeptides comprise the human HPK1 polynucleotideas set forth in SEQ ID NO: 1 (nucleotides 141-2642 of GenBank AccessionNo. NM_007181.5) and the encoded human HPK1 polypeptide (Accession No.NP_009112.1) as set forth in SEQ ID NO: 2. A shorter 821 amino acidisoform of HPK1 exists in humans, the coding sequence and amino acidsequence of which is set forth in SEQ ID NOs: 3 and 1, respectively(nucleotides 141-2606 of GenBank Accession No. NM_001042600.2 andGenBank Accession No. NP_001036065.1, respectively).

HPK1 polypeptides comprise a variety of conserved structural motifs. Forease of reference, such motifs will be discussed as they relate to thelonger human HPK1 isoform, which is set forth in SEQ ID NO:2, comprises833 amino acid residues. HPK1 polypeptides comprise an amino-terminalSte20-like kinase domain that spans amino acid residues 17-293, whichincludes the ATP-binding site from amino acid residues 23-46. The kinasedomain is followed by four proline-rich (PR) motifs that serve asbinding sites for SH3-containing proteins, such as CrkL, Grb2, HIP-55,Gads, Nck, and Crk. The four PR motifs span amino acid residues 308-407,394-402, 432-443, and 468-477, respectively. HPK1 becomes phosphorylatedand activated in response to TCR or BCR stimulation. TCR- andBCR-induced phosphorylation of the tyrosine at position 381, locatedbetween PR₁ and PR₂, mediates binding to SLP-76 in T cells or BLNK in Bcells via a SLP-76 or BLNK SH2 domain, and is required for activation ofthe kinase. A citron homology domain found in the C-terminus of HPK1,approximately spanning residues 495-800, may act as a regulatory domainand may be involved in macromolecular interactions.

The presently disclosed compounds bind directly to HPK1 and inhibit itskinase activity. In some embodiments, the presently disclosed compoundsreduce, inhibit, or otherwise diminish the HPK1-mediated phosphorylationof SLP76 and/or Gads.

The presently disclosed compounds may or may not be a specific HPK1antagonist. A specific HPK1 antagonist reduces the biological activityof HPK1 by an amount that is statistically greater than the inhibitoryeffect of the antagonist on any other protein (e.g., otherserine/threonine kinases). In certain embodiments, the presentlydisclosed compounds specifically inhibit the serine/threonine kinaseactivity of HPK1. In some of these embodiments, the IC₅₀ of the HPK1antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,10%, 0.1%, 0.01%, 0.001%, or less of the IC₅₀ of the HPK1 antagonist foranother serine/threonine kinase or other type of kinase (e.g., tyrosinekinase).

The presently disclosed compounds can be used in a method for inhibitingHPK1. Such methods comprise contacting HPK1 with an effective amount ofa presently disclosed compound. By “contact” is intended bringing thecompound within close enough proximity to an isolated HPK1 enzyme or acell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such thatthe compound is able to bind to and inhibit the activity of HPK1. Thecompound can be contacted with HPK1 in vitro or in vivo viaadministration of the compound to a subject.

Any method known in the art to measure the kinase activity of HPK1 maybe used to determine if HPK1 has been inhibited, including in vitrokinase assays, immunoblots with antibodies specific for phosphorylatedtargets of HPK1, such as SLP76 and Gads, or the measurement of adownstream biological effect of HPK1 kinase activity, such as therecruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, releaseof the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or Tor B cell activation.

The presently disclosed compounds can be used to treat a HPK1-dependentdisorder. As used herein, a “HPK1-dependent disorder” is a pathologicalcondition in which HPK1 activity is necessary for the genesis ormaintenance of the pathological condition. In some embodiments, theHPK1-dependent disorder is cancer.

The presently disclosed compounds also find use in enhancing an immuneresponse in a subject in need thereof. Such methods compriseadministering an effective amount of a presently disclosed compound(i.e., compound of Formula I or Ia or a pharmaceutically acceptablesalt, prodrug, metabolite, or derivative thereof).

As used herein, “enhancing an immune response” refers to an improvementin any immunogenic response to an antigen. Non-limiting examples ofimprovements in an immunogenic response to an antigen include enhancedmaturation or migration of dendritic cells, enhanced activation of Tcells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 Tcell, CD8 T cell) proliferation, enhanced B cell proliferation,increased survival of T cells and/or B cells, improved antigenpresentation by antigen presenting cells (e.g., dendritic cells),improved antigen clearance, increase in production of cytokines by Tcells (e.g., interleukin-2), increased resistance to prostaglandinE2-induced immune suppression, and enhanced priming and/or cytolyticactivity of CD8 T cells.

In some embodiments, the CD8 T cells in the subject have enhancedpriming, activation, proliferation and/or cytolytic activity relative toprior to the administration of the compound of Formula I or Ia or apharmaceutically acceptable salt, prodrug, metabolite, or derivativethereof. In some embodiments, the CD8 T cell priming is characterized byelevated CD44 expression and/or enhanced cytolytic activity in CD8 Tcells. In some embodiments, the CD8 T cell activation is characterizedby an elevated frequency of γ-IFN⁺ CD8 T cells. In some embodiments, theCD8 T cell is an antigen-specific T-cell.

In some embodiments, the antigen presenting cells in the subject haveenhanced maturation and activation relative to prior to theadministration of the compound of Formula I or Ia or a pharmaceuticallyacceptable salt, prodrug, metabolite, or derivative thereof. In someembodiments, the antigen presenting cells are dendritic cells. In someembodiments, the maturation of the antigen presenting cells ischaracterized by an increased frequency of CD83⁺ dendritic cells. Insome embodiments, the activation of the antigen presenting cells ischaracterized by elevated expression of CD80 and CD86 on dendriticcells.

In some embodiments, the serum levels of cytokine IL-10 and/or chemokineIL-8, a human homolog of murine KC, in the subject are reduced relativeto prior to the administration of the compound of Formula I or Ia or apharmaceutically acceptable salt, prodrug, metabolite, or derivativethereof.

Engagement of the TCR leads to HPK1 activation, which functions as anegative regulator of TCR-induced AP-1 response pathway. It is believedthat HPK1 negatively regulates T cell activation by reducing thepersistence of signaling microclusters by phosphorylating SLP76 atSer376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254,which leads to the recruitment of 14-3-3 proteins that bind to thephosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complexfrom LAT-containing microclusters, which leads to T cell dysfunction,including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol195(5):839-853).

The term “dysfunction” in the context of immune dysfunction, refers to astate of reduced immune responsiveness to antigenic stimulation. Theterm includes the common elements of both exhaustion and/or anergy inwhich antigen recognition may occur, but the ensuing immune response isineffective to control infection or tumor growthours.

The term “dysfunctional”, as used herein, also includes refractory orunresponsive to antigen recognition, specifically, impaired capacity totranslate antigen recognition into down-stream T-cell effectorfunctions, such as proliferation, cytokine production (e.g., IL-2,γ-IFN) and/or target cell killing.

The term “anergy” refers to the state of unresponsiveness to antigenstimulation resulting from incomplete or insufficient signals deliveredthrough the T-cell receptor (e.g. increase in intracellular Ca⁺² in theabsence of ras-activation). T cell anergy can also result uponstimulation with antigen in the absence of co-stimulation, resulting inthe cell becoming refractory to subsequent activation by the antigeneven in the context of costimulation. The unresponsive state can oftenbe overriden by the presence of Interleukin-2. Anergic T-cells do notundergo clonal expansion and/or acquire effector functions.

The term “exhaustion” refers to T cell exhaustion as a state of T celldysfunction that arises from sustained TCR signaling that occurs duringmany chronic infections and cancer. It is distinguished from anergy inthat it arises not through incomplete or deficient signaling, but fromsustained signaling. It is defined by poor effector function, sustainedexpression of inhibitory receptors and a transcriptional state distinctfrom that of functional effector or memory T cells. Exhaustion preventsoptimal control of infection and tumors. Exhaustion can result from bothextrinsic negative regulatory pathways (e.g., immunoregulatorycytokines) as well as cell intrinsic negative regulatory (costimulatory)pathways (PD-1, B7-H3, B7-H4, etc.).

In some embodiments, administration of a compound of Formula I or Ia ora pharmaceutically acceptable salt, prodrug, metabolite, or derivativethereof to a subject results in an enhancement of T cell function.

“Enhancing T cell function” means to induce, cause or stimulate a T cellto have a sustained or amplified biological function, or renew orreactivate exhausted or inactive T cells. Examples of enhancing T cellfunction include: increased secretion of cytokines (e.g., γ-interferon,IL-2, IL-12, and TNFα), increased proliferation, increased antigenresponsiveness (e.g., viral, pathogen, or tumor clearance) relative tosuch levels before the intervention, and increased effector granuleproduction by CD8 T cells, such as granzyme B. In one embodiment, thelevel of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%,100%, 120%, 150%, 200%. The manner of measuring this enhancement isknown to one of ordinary skill in the art.

Accordingly, the presently disclosed compounds of Formula I or Ia orpharmaceutically acceptable salts, prodrugs, metabolites, or derivativesthereof are useful in treating T cell dysfunctional disorders. A “T celldysfunctional disorder” is a disorder or condition of T cellscharacterized by decreased responsiveness to antigenic stimulation. In aparticular embodiment, a T cell dysfunctional disorder is a disorderthat is specifically associated with increased kinase activity of HPK1.In another embodiment, a T cell dysfunctional disorder is one in which Tcells are anergic or have decreased ability to secrete cytokines,proliferate, or execute cytolytic activity. In a specific aspect, thedecreased responsiveness results in ineffective control of a pathogen ortumor expressing an immunogen. Examples of T cell dysfunctionaldisorders characterized by T-cell dysfunction include unresolved acuteinfection, chronic infection and tumor immunity.

Thus, the presently disclosed compounds can be used in treatingconditions where enhanced immunogenicity is desired, such as increasingtumor immunogenicity for the treatment of cancer.

“Immunogenecity” refers to the ability of a particular substance toprovoke an immune response. Tumors are immunogenic and enhancing tumorimmunogenicity aids in the clearance of the tumor cells by the immuneresponse.

“Tumor immunity” refers to the process in which tumors evade immunerecognition and clearance. Thus, as a therapeutic concept, tumorimmunity is “treated” when such evasion is attenuated, and the tumorsare recognized and attacked by the immune system. Examples of tumorrecognition include tumor binding, tumor shrinkage and tumor clearance.

In one aspect, provided herein is a method for treating of cancer in asubject in need thereof comprising administering to the subject aneffective amount of a compound of Formula I or Ia or a pharmaceuticallyacceptable salt, prodrug, metabolite, or derivative thereof. In someembodiments, the subject has melanoma. The melanoma may be at earlystage or at late stage. In some embodiments, the subject has colorectalcancer. The colorectal cancer may be at early stage or at late stage. Insome embodiments, the subject has non-small cell lung cancer. Thenon-small cell lung cancer may be at early stage or at late stage. Insome embodiments, the subject has pancreatic cancer. The pancreaticcancer may be at early stage or late state. In some embodiments, thesubject has a hematological malignancy. The hematological malignancy maybe at early stage or late stage. In some embodiments, the subject hasovarian cancer. The ovarian cancer may be at early stage or at latestage. In some embodiments, the subject has breast cancer. The breastcancer may be at early stage or at late stage. In some embodiments, thesubject has renal cell carcinoma. The renal cell carcinoma may be atearly stage or at late stage. In some embodiments, the cancer haselevated levels of T-cell infiltration.

The presently disclosed compounds may be administered in any suitablemanner known in the art. In some embodiments, the compound of Formula Ior Ia or a pharmaceutically acceptable salt, prodrug, metabolite, orderivative thereof is administered intravenously, intramuscularly,subcutaneously, topically, orally, transdermally, intraperitoneally,intraorbitally, by implantation, by inhalation, intrathecally,intraventricularly, intratumorally, or intranasally.

In some embodiments, the HPK1 antagonist is administered continuously.In other embodiments, the HPK1 antagonist is administeredintermittently. Moreover, treatment of a subject with an effectiveamount of a HPK1 antagonist can include a single treatment or caninclude a series of treatments.

It is understood that appropriate doses of the active compound dependsupon a number of factors within the knowledge of the ordinarily skilledphysician or veterinarian. The dose(s) of the active compound will vary,for example, depending upon the age, body weight, general health,gender, and diet of the subject, the time of administration, the routeof administration, the rate of excretion, and any drug combination.

It will also be appreciated that the effective dosage of a compound ofFormula I or Ia or a pharmaceutically acceptable salt, prodrug,metabolite, or derivative thereof used for treatment may increase ordecrease over the course of a particular treatment. Changes in dosagemay result and become apparent from the results of diagnostic assays.

In some embodiments, the HPK1 antagonist is administered to the subjectat a dose of between about 0.001 μg/kg and about 1000 mg/kg, includingbut not limited to about 0.001 μg/kg, about 0.01 μg/kg, about 0.05μg/kg, about 0.1 μg/kg, about 0.5 μg/kg, about 1 μg/kg, about 10 μg/kg,about 25 μg/kg, about 50 μg/kg, about 100 μg/kg, about 250 μg/kg, about500 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg,about 50 mg/kg, about 100 mg/kg, and about 200 mg/kg.

In some embodiments, provided is a method for treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a compound of Formula I or Ia or a pharmaceuticallyacceptable salt, prodrug, metabolite, or derivative thereof, furthercomprising administering an additional therapy. The additional therapymay be radiation therapy, surgery (e.g., lumpectomy and a mastectomy),chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy,immunotherapy, bone marrow transplantation, nanotherapy, monoclonalantibody therapy, or a combination of the foregoing. The additionaltherapy may be in the form of adjuvant or neoadjuvant therapy. In someembodiments, the additional therapy is the administration of ananti-metastatic agent. In some embodiments, the additional therapy isthe administration of side-effect limiting agents (e.g., agents intendedto lessen the occurrence and/or severity of side effects of treatment,such as anti-nausea agents, etc.). In some embodiments, the additionaltherapy is radiation therapy. In some embodiments, the additionaltherapy is surgery. In some embodiments, the additional therapy is acombination of radiation therapy and surgery. In some embodiments, theadditional therapy is gamma irradiation. In some embodiments, theadditional therapy is therapy targeting the PI3K/AKT/mTOR pathway, HSP90inhibitor, tubulin inhibitor, apoptosis inhibitor, and/orchemopreventative agent.

The additional therapy may be one or more of a chemotherapeutic agent.Thus, the method of treating cancer can comprise administering thepresently disclosed HPK1 antagonists in conjunction with at least onechemotherapeutic agent.

As used herein, “in conjunction with” refers to administration of onetreatment modality in addition to another treatment modality. As such,“in conjunction with” refers to administration of one treatment modalitybefore, during, or after administration of the other treatment modalityto the subject.

For example, the HPK1 antagonist and chemotherapeutic agent may beadministered sequentially (at different times) or concurrently (at thesame time). The HPK1 antagonist and chemotherapeutic agent may beadministered by the same route of administration or by different routesof administration.

In certain embodiments, the HPK1 antagonist is administered inconjunction with another immunotherapy. For example, the HPK1 antagonistcan be combined with a chemotherapeutic agent or biologic that targetsthe PDL1/PD1 pathway. A known inhibitory checkpoint pathway involvessignaling through PD-1 receptors. The programmed-death 1 (PD-1) receptorand its ligands PD-L1 and PD-L2 are part of the same family ofcoregulatory molecules as CTLA-4.—See more at:http://www.onclive.com/web-exclusives/the-role-of-anti-pd-11-immunotherapy-in-cancer/2#sthash.cGfYalTl.dpufChemotherapeutic agents or biologics that block PD-L1 binding to PD-1and CD80 can prevent PD-L1-mediated inhibition/suppression of T-cellactivation. Programmed cell death ligand-1 (PD-L1) is widely expressedon antigen-presenting cells (APC) and other immune cells. It isupregulated on tumor cells from a broad range of human cancers, and hasbeen implicated with inhibition of antitumor T-cell immunity. PD-L1 is acell surface protein that binds to the receptors PD-1 and CD80 onactivated T cells, B cells, and other myeloid cells. PD-L1 binding toPD-1 on activated T-cells has been found to interfere with T-cellproliferation and inhibit immune responses. Overexpression of PD-L1 oncancer cells may allow these cells to avoid immune detection andelimination. High levels of PD-L1 expression on tumor cells have beenassociated with increased tumor aggressiveness and a poor prognosis.Chemotherapeutic agents or biologics that block PD-L1 binding to PD-1include anti-PD-L1 antibodies, such as durvalumab, nivolumab,pidlizumab, MPDL3280A, MK-3475 and BMS-936559, among others.

In another example, the HPK1 antagonist can be combined with achemotherapeutic agent or biologic that targets OX40 and its ligand,OX40L, are members of the TNF superfamily. OX40 is expressed onactivated CD4(+) and CD8(+) T cells as well as on a number of otherlymphoid and non-lymphoid cells. Costimulatory signals from OX40 to aconventional T cell promote division and survival, augmenting the clonalexpansion of effector and memory populations as they are being generatedto antigen. OX40 additionally suppresses the differentiation andactivity of T-regulatory cells, further amplifying this process. OX40and OX40L also regulate cytokine production from T cells,antigen-presenting cells, natural killer cells, and natural killer Tcells, and modulate cytokine receptor signaling. As one of the mostprominent costimulatory molecules known to control T cells, stimulatingOX40 has been shown be a target for therapeutic immunization strategiesfor cancer. Certain OX40 agonists include GBR 830, and those disclosedin Linch, et al., Frontiers in Oncology, v. 5, pp. 1-10 (2015), hereinincorporated by reference in its entirety.

In some embodiments, the invention also provides compounds of Formula Ior Ia described herein or pharmaceutical compositions described hereinfor use in a method for inhibiting HPK1 as described herein, in a methodfor enhancing an immune response in a subject in need thereof asdescribed herein and/or in a method for treating a HPK1-dependentdisorder as described herein.

In some embodiments, the invention also provides compounds of Formula Ior Ia described herein or pharmaceutical compositions described hereinfor use in a method for inhibiting HPK1 as described herein.

In some embodiments, the invention also provides compounds of Formula Ior Ia described herein or pharmaceutical compositions described hereinfor use in a method for enhancing an immune response in a subject inneed thereof as described herein.

In some embodiments, the invention also provides compounds of Formula Ior Ia described herein or pharmaceutical compositions described hereinfor use in a method for treating a HPK1-dependent disorder as describedherein.

In some embodiments, the invention also provides the use of a compoundof Formula I or Ia described herein or a pharmaceutical compositiondescribed herein for the manufacture of a medicament for inhibitingHPK1, a medicament for enhancing an immune response in a subject in needthereof and/or a medicament for treating a HPK1-dependent disorder.

In some embodiments, the invention also provides the use of a compoundof Formula I or Ia described herein or a pharmaceutical compositiondescribed herein for the manufacture of a medicament for inhibitingHPK1.

In some embodiments, the invention also provides the use of a compoundof Formula I or Ia described herein or a pharmaceutical compositiondescribed herein for the manufacture of a medicament for enhancing animmune response in a subject in need thereof.

In some embodiments, the invention also provides the use of a compoundof Formula I or Ia described herein or a pharmaceutical compositiondescribed herein for the manufacture of a medicament treating aHPK1-dependent disorder.

In some embodiments, the invention also provides the use of compounds ofFormula I or Ia described herein or pharmaceutical compositionsdescribed herein in a method for inhibiting HPK1 as described herein, ina method for enhancing an immune response in a subject in need thereofas described herein and/or in a method for treating a HPK1-dependentdisorder as described herein.

In some embodiments, the invention also provides the use of compounds ofFormula I or Ia described herein or pharmaceutical compositionsdescribed herein in a method for inhibiting HPK1 as described herein.

In some embodiments, the invention also provides the use of compounds ofFormula I or Ia described herein or pharmaceutical compositionsdescribed herein in a method for enhancing an immune response in asubject in need thereof as described herein.

In some embodiments, the invention also provides the use of compounds ofFormula I or Ia described herein or pharmaceutical compositionsdescribed herein in a method for treating a HPK1-dependent disorder asdescribed herein.

In some embodiments, the treatment results in a sustained response inthe subject after cessation of the treatment. “Sustained response”refers to the sustained effect on reducing tumor growth after cessationof a treatment. For example, the tumor size may remain the same orsmaller as compared to the size at the beginning of the administrationphase. In some embodiments, the sustained response has a duration atleast the same as the treatment duration, at least 1.5×, 2.0×, 2.5×, or3.0× length of the treatment duration.

The treatment methods disclosed herein may result in a partial orcomplete response. As used herein, “complete response” or “CR” refers todisappearance of all target lesions; “partial response” or “PR” refersto at least a 30% decrease in the sum of the longest diameters (SLD) oftarget lesions, taking as reference the baseline SLD; and “stabledisease” or “SD” refers to neither sufficient shrinkage of targetlesions to qualify for PR, nor sufficient increase to qualify for PD,taking as reference the smallest SLD since the treatment started. Asused herein, “overall response rate” (ORR) refers to the sum of completeresponse (CR) rate and partial response (PR) rate.

The treatment methods disclosed herein can lead to an increase inprogression free survival and overall survival of the subjectadministered the HPK1 antagonist. As used herein, “progression freesurvival” (PFS) refers to the length of time during and after treatmentduring which the disease being treated (e.g., cancer) does not getworse. Progression-free survival may include the amount of time patientshave experienced a complete response or a partial response, as well asthe amount of time patients have experienced stable disease.

As used herein, “overall survival” refers to the percentage of subjectsin a group who are likely to be alive after a particular duration oftime.

In some embodiments, the subject that is administered a HPK1 antagonistis a mammal, such as domesticated animals (e.g., cows, sheep, cats,dogs, and horses), primates (e.g., humans and non-human primates such asmonkeys), rabbits, and rodents (e.g., mice and rats). In someembodiments, the subject treated is a human.

The subject in need of treatment for cancer may be a persondemonstrating symptoms of cancer, one that has been diagnosed withcancer, a subject that is in remission from cancer, or a subject havingan increased risk for developing cancer (e.g., a genetic predisposition,certain dietary or environmental exposures).

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES Materials and Methods

Method A: Experiments performed on an Agilent 1100 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentSunFire-C18 3.5 μm, 4.6×50 column and a 2.0 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 0.05% TFA(solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), ramping upto 100% solvent B over 1.3 minutes. The final solvent system was heldconstant for a further 1.2 minutes.

Method B: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentSunFire-C18 3.5 4.6×50 column and a 2.0 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.01% TFA (solvent A)and 5% acetonitrile with 0.01% TFA (solvent B), ramping up to 5% solventA and 95% solvent B over 1.4 minutes. The final solvent system was heldconstant for a further 1.0 minute.

Method C: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentXbridge-C18, 3.5 4.6×50 mm column and a 1.8 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 10 mM NH₄HCO₃(solvent A) and 5% acetonitrile (solvent B), ramping up to 5% solvent Aand 95% solvent B over 1.3 minutes. The final solvent system was heldconstant for a further 1.2 minutes.

Method D: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentXbridge-C18, 3.5 4.6×50 mm column and a 1.8 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 10 mM NH₄HCO₃(solvent A) and 5% acetonitrile (solvent B), ramping up to 5% solvent Aand 95% solvent B over 1.6 minutes. The final solvent system was heldconstant for a further 1.0 minute.

Method E: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentSunFire-C18 3.5 4.6×50 column and a 2.0 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.01% TFA (solvent A)and 5% acetonitrile with 0.01% TFA (solvent B), ramping up to 5% solventA and 95% solvent B over 1.5 minutes. The final solvent system was heldconstant for a further 1.0 minute.

Method F: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentXbridge-C18, 3.5 μm, 4.6×50 mm column and a 1.8 ml/minute flow rate. Thesolvent system was a gradient starting with 90% water with 10 mM NH₄HCO₃(solvent A) and 10% acetonitrile (solvent B), ramping up to 5% solvent Aand 95% solvent B over 1.5 minutes. The final solvent system was heldconstant for a further 1.0 minute.

Method G: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an AgilentXbridge-C18, 3.5 μm, 4.6×50 mm column and a 1.8 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 10 mM NH₄HCO₃(solvent A) and 5% acetonitrile (solvent B), ramping up to 5% solvent Aand 95% solvent B over 1.4 minutes. The final solvent system was heldconstant for a further 1.0 minute.

Method H: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using Gemini-Nx 3u,C18, 3 μm, 4.6×50 mm column and a 1.8 ml/minute flow rate. The solventsystem was a gradient starting with 90% water with 10 mM NH₄HCO₃(solvent A) and 10% acetonitrile (solvent B), ramping up to 5% solvent Aand 95% solvent B over 1.5 minutes. The final solvent system was heldconstant for a further 1.0 minute.

Method I: Experiments performed on an Agilent 1200 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using XBridge-C18, 3.5μm, 4.6×50 mm column and a 1.8 ml/minute flow rate. The solvent systemwas a gradient starting with 95% water with 10 mM NH₄HCO₃ (solvent A)and 5% acetonitrile (solvent B), ramping up to 5% solvent A and 95%solvent B over 1.6 minutes. The final solvent system was held constantfor a further 1.0 minute.

Method J: Experiments performed on an Agilent 1290 UHPLC coupled withAgilent MSD (6140) mass spectrometer using ESI as ionization source. TheLC separation was using a Phenomenex XB-C18, 1.7 μm, 50×2.1 mm columnwith a 0.4 ml/minute flow rate. Solvent A is water with 0.1% FA andsolvent B is acetonitrile with 0.1% FA. The gradient consisted with2-98% solvent B over 7 min and hold 98% B for 1.5 min followingequilibration for 1.5 min. LC column temperature is 40° C. UV absorbancewas collected at 220 nm and 254 nm and mass spec full scan was appliedto all experiments.

Method J*: Experiments were performed on a Shimadzu 20AD HPLC withShimadzu LCMS2020 mass spectrometer using ESI as ionization source, aShim-Pack XR-ODS C18 2.2 3.0×50 column, and a 1.2 ml/minute flow rate.The solvent system was a gradient starting with 95% water with 0.05% TFA(solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), ramping upto 95% solvent B over 2.0 minutes. The final solvent system was heldconstant for a further 0.7 minutes.

Method K: Experiments performed on a Shimadzu LC-20AD with LCMS-2020mass spectrometer using ESI as ionization source using a Shim-PackXR-ODS 2.2 3.0×50 column and a 1.2 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.05% TFA (solvent A)and 5% acetonitrile with 0.05% TFA (solvent B), ramping up to 5% solventA and 95% solvent B over 2.0 minutes. The final solvent system was heldconstant for a further 0.7 minute.

Method K*: Experiments performed on a Shimadzu 20AD HPLC with ShimadzuLCMS-2020 mass spectrometer using ESI as ionization source using aShim-Pack XR-ODS 2.2 3.0×50 column and a 1.2 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 0.05% TFA(solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), ramping upto 95% solvent B over 2.0 minutes. The final solvent system was heldconstant for a further 0.7 minute.

Method L: Experiments performed on a Shimadzu LC-30AD with LCMS-2020mass spectrometer using ESI as ionization source using an AscentisExpress C18 2.7 3.0×50 mm column and a 1.0 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 0.05% TFA(solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), ramping upto 5% solvent A and 95% solvent B over 2.0 minutes. The final solventsystem was held constant for a further 0.7 minute.

Method L*: Experiments performed on a Shimadzu 30AD HPLC with ShimadzuLCMS-2020 mass spectrometer using ESI as ionization source using anAscentis Express C18 2.7 μm, 2.1×50 column and a 1.0 ml/minute flowrate. The solvent system was a gradient starting with 95% water with0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B),ramping up to 95% solvent B over 2.0 minutes. The final solvent systemwas held constant for a further 0.7minute.

Method M: Experiments performed on a Shimadzu LC-20ADXR with LCMS-2020mass spectrometer using ESI as ionization source using a poroshellHPH-C18, 2.7 μm, 3.0×50 column and a 1.2 ml/minute flow rate. Thesolvent system was a gradient starting with 95% water with 5 mM NH₄HCO₃(solvent A) and 5% acetonitrile (solvent B), ramping up to 95% solvent Bover 2.0 minutes. The final solvent system was held constant for afurther 0.7 minutes.

Method M*: Experiments performed on a Shimadzu 20AD XR HPLC withShimadzu LCMS2020 mass spectrometer using ESI as ionization source usinga poroshell HPH-C18, 2.7 μm, 3.0×50 column and a 1.2 ml/minute flowrate. The solvent system was a gradient starting with 95% water with 5mM Ammonium bicarbonate (solvent A) and 5% acetonitrile (solvent B),ramping up to 95% solvent B over 2.0 minutes. The final solvent systemwas held constant for a further 0.7 minutes.

Method N: Experiments performed on a Shimadzu LC-30AD with LCMS-2020mass spectrometer using ESI as ionization source using a CAPCELL COREC18, 2.7 μm, 2.1×50 mm column and a 1.0 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.1% FA (solvent A)and 5% acetonitrile with 0.1% FA (solvent B), ramping up to 5% solvent Aand 95% solvent B over 2.0 minutes. The final solvent system was heldconstant for a further 0.7 minute.

Method N*: Experiments performed on an Agilent 1290 UHPLC coupled withAgilent MSD (6140) mass spectrometer using ESI as ionization source. TheLC separation used a Phenomenex XB-C18, 1.7 μm, 50×2.1 mm column with a0.4 ml/minute flow rate. Solvent A was water with 0.1% FA and solvent Bwas acetonitrile with 0.1% FA. The gradient consisted with 2-98% solventB over 7 min and hold 98% B for 1.5 min following equilibration for 1.5min. LC column temperature is 40° C. UV absorbance was collected at 220nm and 254 nm and mass spec full scan was applied to all experiment.

Method O: Experiments performed on a Shimadzu LC-30AD with LCMS-2020mass spectrometer using ESI as ionization source using a kinetex EVOC18, 2.7 μm, 2.1×50 column and a 1.2 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 6.5 mM NH₄HCO₃(solvent A) and 5% acetonitrile (solvent B), ramping up to 95% solvent Bover 2.0 minutes. The final solvent system was held constant for afurther 0.7 minutes.

Method O*: Experiment was performed on a Waters Acquity UPLC with WatersLCT Premier XE mass spectrometer using ESI ionization. The LC separationwas using an Acquity UPLC BEH C18, 1.7 μm, 2.1×50 mm column and a 0.6ml/min flow rate. MPA (mobile phase A) was water with 0.05% TFA and MPB(mobile phase B) was acetonitrile with 0.05% TFA. The gradient consistedwith 2-98% MPB over 5 min and hold 98% B for 0.5 min followingequilibration for 0.5 min. LC column temperature is 40° C. UV data wascollected at 220 nm and 254 nm and mass spec full scan was applied toall experiments.

Method P: Experiments performed on a Shimadzu LC-20AD with LCMS-2010mass spectrometer using ESI as ionization source using a Shim-PackXR-ODS 2.2 μm, 3.0×50 column and a 1.2 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.05% TFA (solvent A)and 5% acetonitrile with 0.05% TFA (solvent B), ramping up to 5% solventA and 95% solvent B over 2.0 minutes. The final solvent system was heldconstant for a further 0.7 minute. LC column temperature is 40° C. UVabsorbance was collected at 220 nm and 254 nm and mass spec full scanwas applied to all experiments.

Compound Syntheses Synthetic Intermediates Example I.1 Intermediate 1:6-bromo-8-chloro-isoquinolin-3-amine

Step 1: methyl 2,2-diethoxyethanimidate

To a stirred solution of diethoxyacetonitrile (7.0 g, 54.2 mmol) in drymethanol (50 mL) was added a solution of sodium methoxide in methanol(4.2 mL, 20%, 8.4 mmol). After the addition, the reaction mixture wasstirred at room temperature for 48 hours. The reaction was concentratedto dryness and the residue was taken up in chloroform and the organiclayer washed with water, dried and concentrated to give methyl2,2-diethoxyethanimidate (8.37 g, 95% yield) as a colorless oil, whichwas used in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 7.95 (s, 1H), 4.82 (s, 1H), 3.65 (s, 3H), 3.51 (q, J=7.2 Hz,4H), 1.14 (t, J=7.2 Hz, 6H).

Step 2: 4-bromo-2-chloro-phenyl)methanamine

To a 50 mL round bottom flask was added BH₃-THF (1.0 M in THF, 32.5 mL,32.5 mmol) and 4-bromo-2-chlorobenzonitrile (1.76 g, 8.13 mmol) in THF(10 mL). The mixture was heated to reflux for 2 hours. The reactionmixture was quenched by the addition of an aqueous HCl solution (10 wt %yield). The pH was adjusted to 8 by adding an aqueous solution of NaOH(5 wt % yield) and extracted with dichloromethane. The organic layer wasdried, filtered and concentrated to afford(4-bromo-2-chloro-phenyl)methanamine (1.62 g, 90% yield), which was usedin the next step without further purification. LCMS (ESI) [M+H]⁺=220.0.

Step 3: N-[(4-bromo-2-chloro-phenyl)methyl]-2,2-diethoxy-acetamidine

Methyl 2,2-diethoxyethanimidate (2.7 g, 16.8 mmol) was added drop-wiseto a stirred solution of (4-bromo-2-chloro-phenyl)methanamine (2.47 g,11.2 mmol) in methanol (100 mL). The mixture was stirred for 2 hours atroom temperature. The reaction was concentrated to dryness and theresidue was taken up in dichloromethane. The organic layer washed withbrine, dried (Na₂SO₄) and concentrated to crudeN-[(4-bromo-2-chloro-phenyl)methyl]-2,2-diethoxy-acetamidine (3.76 g,89% yield) as a white solid, which was used in the next step withoutfurther purification. LCMS (ESI) [M+H]⁺=349.0

Step 4: 6-bromo-8-chloro-isoquinolin-3-amine

To the crudeN-[(4-bromo-2-chloro-phenyl)methyl]-2,2-diethoxy-acetamidine (1.9 g,5.05 mmol) was added conc. H₂SO₄ (14.9g, 152 mmol) at 0° C. under N₂.The reaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was cooled to 0° C. and a 1 M NaOH solution added toadjust the pH to 7. The residue was extracted with dichloromethane. Thecombined organic layers were washed with brine and dried (Na₂SO₄) beforeconcentration to dryness. The crude was purified by flash columnchromatography (ethyl acetate:petroleum ether=1:3) to give6-bromo-8-chloro-isoquinolin-3-amine (410 mg, 33% yield) as a yellowsolid. LCMS (ESI) [M+H]⁺=256.9

Example I.2 Intermediate 2: N-(6-bromo-8-chloro-3soquinolyl)cyclopropanecarboxamide

To a cooled (0° C.) mixture of 6-bromo-8-chloro-isoquinolin-3-amine (900mg, 2.1 mmol) and pyridine (166 mg, 2.1 mmol) in dichloromethane (10 mL)was added cyclopropanecarbonyl chloride (263 mg, 2.52 mmol). Thereaction was stirred at 0° C. for 1 hour. The reaction mixture wasquenched by the addition of a saturated aqueous solution of NH₄Cl andextracted with dichloromethane. The organic was dried, filtered andconcentrated. The crude was purified by flash column chromatography (40%dichloromethane in petroleum ether) to give(N-(6-bromo-8-chloro-3-isoquinolyl)cyclopropanecarboxamide (550 mg, 74%yield) as a yellow solid. LCMS (ESI) [M+H]⁺=324.9

Example I.3 Intermediate 3: 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine

Step 1: 4-amino-2-chloro-3-fluorobenzonitrile

To a sealed tube were added copper (I) cyanide (1.2 g, 13.37 mmol),4-bromo-3-chloro-2-fluoroaniline (1 g, 4.46 mmol) and1-methyl-2-pyrrolidinone (8 mL). The mixture was heated at 170° C. for 1hour in a microwave reactor. The reaction mixture was quenched byaddition of a saturated solution of NH₄Cl (20 mL) and filtered. Thefiltrate was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine (3×10 mL), dried with Na₂SO₄,filtered through a pad of silica gel, and concentrated to dryness togive 4-amino-2-chloro-3-fluorobenzonitrile (700 mg, 92% yield) as ayellow solid. LCMS (ESI) [M+H]+=171.1.

Step 2: 2-chloro-3-fluoro-4-iodobenzonitrile

To a suspension of CuI (3341 mg, 17.59 mmol) in acetonitrile (50 mL) wasadded tert-butyl nitrite (1811 mg, 17.59 mmol) at 65° C. under N₂. Themixture was stirred at 65° C. for 10 minutes. Then4-amino-2-chloro-3-fluorobenzonitrile (2 g, 11.73 mmol) was added to thereaction mixture. The mixture was stirred at 65° C. for 12 hours. Themixture was quenched with saturated aqueous Na₂S₂O₄ (30 mL) and aqueousNH₄Cl (30 mL) and extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with brine (2 ×10 mL), dried over Na₂SO₄ andfiltered. The filtrate was concentrated to give crude product, which waspurified by flash chromatography (petroleum ether/ethyl acetate=5/1) togive 2-chloro-3-fluoro-4-iodobenzonitrile (1 g, 30% yield) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J=5.6, 8.2 Hz, 1H), 7.22 (dd,J=1.4, 8.2 Hz, 1H).

Step 3: (2-chloro-3-fluoro-4-iodophenyl)methanamine

2-Chloro-3-fluoro-4-iodobenzonitrile (1 g, 3.55 mmol) was added to asolution of borane-THF (35.53 mL, 1 M in THF, 35.53 mmol) in THF (30 mL)at 0° C. The mixture was then warmed to room temperature and stirredovernight. The reaction solution was quenched by the dropwise additionof a solution of HCl (6 M, 2 mL). The mixture was neutralized with anaqueous solution of NaHCO₃ to pH=8 and extracted with dichloromethane(2×200 mL). The combined organic layer was washed with water (2×10 mL)and brine (1×10 mL), dried (Na₂SO₄), filtered and concentrated to give(2-chloro-3-fluoro-4-iodophenyl)methanamine (400 mg, crude), which wasused directly in the next step without further purification. LCMS (ESI)[M+H]⁺=285.9.

Step 4: N-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide

To a solution of methyl 2,2-diethoxyacetimidate (0.3 g, 1.88 mmol) inmethanol (5 mL) was added (2-chloro-3-fluoro-4-iodophenyl)methanamine(250 mg, 0.88 mmol). The reaction mixture was stirred at 25° C. for 12hours, and then concentrated to dryness. The residue was taken up indichloromethane (20 mL), washed with water (2×10 mL) then brine, dried(MgSO₄), filtered and concentrated to giveN-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide (360 mg,crude) as a yellow solid. It was directly used to the next step withoutpurification. LCMS (ESI) [M+H]⁺=415.0.

Step 5: 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine

A solution ofN-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide (0.36 g,0.87 mmol) and conc. H₂SO₄ (10 mL, 26.05 mmol) was stirred at 60° C. for12 hours. The mixture was cooled to 0° C. and NaOH was added to adjustto pH 9. The residue was extracted with dichloromethane (5×100 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated to give 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine(0.25 g, crude) as a yellow solid, which was directly used to the nextstep. LCMS (ESI) [M+H]⁺=322.9. ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H),8.08 (d, J=5.6 Hz, 1H), 6.70 (s, 1H).

Example I.4 Intermediate 4: 7-bromo-8-chloro-6-iodoisoquinolin-3-amine

Step 1: 4-amino-3-bromo-2-chlorobenzonitrile

To a solution of 4-amino-2-chlorobenzonitrile (1.5 g, 9.83 mmol) inacetonitrile (30 mL) was added1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (1.5 g, 5.25 mmol). Thesolution was stirred at 25° C. for 2 hours. The reaction was quenched byaddition with a saturated solution of NaHSO₃ (30 mL) and extracted withethyl acetate (50 mL×2). The organic layer was concentrated. The crudeproduct was purified by flash chromatography (10% ethyl acetate inpetroleum ether) to give a mixture of4-amino-3-bromo-2-chlorobenzonitrile and4-amino-5-bromo-2-chlorobenzonitrile (850 mg, 5/2 ratio ofregio-isomers, 26% yield) as a yellow solid. The mixture would be useddirectly at next step. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (s, 1H), 7.38 (d,J=8.4 Hz, 2.6H), 6.80 (s, 1H), 6.65 (d, J=8.4 Hz, 2.6H), 4.81(bs, 5H),4.71 (bs, 2H).

Step 2: 3-bromo-2-chloro-4-iodobenzonitrile

To a suspension of CuI (51.63 g, 271.74 mmol) in acetonitrile (300 mL)was added tert-butyl nitrite (33.59 g, 326.09 mmol). The mixture wasstirred at 65° C. for 10 minutes. A mixture of4-amino-3-bromo-2-chlorobenzonitrile and4-amino-5-bromo-2-chlorobenzonitrile (3/4 ratio, 25 g, 108.7 mmol) wasadded to the reaction mixture. The mixture was stirred at 65° C. for 12hours. The mixture was quenched with saturated Na₂S₂O₄ solution (30 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (10 mL), dried over by Na₂SO₄ and filtered. Thefiltrate was concentrated and purified by flash column chromatography(5% ethyl acetate in petroleum ether) to give3-bromo-2-chloro-4-iodobenzonitrile (5 g, 31% yield) as a yellow solid.¹H NMR (400 MHz, CDCl₃) 7.91(d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H).

Step 3: (3-bromo-2-chloro-4-iodophenyl)methanamine

To a solution of 3-bromo-2-chloro-4-iodobenzonitrile (3 g, 8.76 mmol) inTHF (30 mL) was added borane-THF (30 mL, 1 M in THF, 30 mmol). Themixture was stirred at 65° C. for 3 h under N₂. The mixture was quenchedby addition of methanol (10 mL) and HCl (12 N, 10 mL). The reaction wasconcentrated to dryness. The residue was taken up in ethyl acetate (100mL) and extracted with water (50 mL×2). The organic layer was discardedand the pH of the aqueous layer was adjusted to pH 9 by adding asaturated NaHCO₃ solution. The mixture was extracted with ethyl acetate(50 mL×3). The combined organic layers were washed with water (10 mL×2)then brine (10 mL), dried (Na₂SO₄), filtered and concentrated to give(3-bromo-2-chloro-4-iodophenyl)methanamine (3 g, 99% yield) as a yellowoil. It was be used directly at next step. LCMS (ESI) [M+H]⁺=345.9.

Step 4: N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide

To a solution of (3-bromo-2-chloro-4-iodophenyl)methanamine (2.5 g, 7.22mmol) in methanol (20 mL) was added methyl 2,2-diethoxyacetimidate (3.75g, 23.26 mmol). The solution was stirred at 25° C. for 12 hours. Thereaction was concentrated to dryness. The residue was dissolved indichloromethane (20 mL), washed with water and brine, dried over MgSO₄,filtered and concentrated to giveN-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide (3 g, 87%yield) as a yellow solid. It was used directly at next step. LCMS (ESI)[M+H]⁺=474.9.

Step 5: 7-bromo-8-chloro-6-iodoisoquinolin-3-amine

A mixture of sulfuric acid (10 mL) andN-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide (3 g, 6.31mmol) was stirred at 60° C. for 12 hours. The reaction mixture wascooled to 0° C. and then NaOH solution was added to adjust the pH to 9.The residue was extracted with dichloromethane (100 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give 7-bromo-8-chloro-6-iodoisoquinolin-3-amine (2.4 g,99% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=382.8. ¹H NMR (400 MHz,DMSO-d₆): δ 8.99 (s, 1H), 8.32 (s, 1H), 6.56 (s, 1H), 6.49 (s, 2H).

Example I.5 Intermediate 5: 7-bromo-8-chloroisoquinolin-3-amine

Step 1: (3-bromo-2-chlorophenyl)methanamine

A mixture of 1-bromo-2-chloro-3-methylbenzene (1.0 g, 4.87 mmol), NBS(1.3 g, 7.3 mmol), and benzoyl peroxide (11 mg, 0.05 mmol) in carbontetrachloride (10 mL) was heated at 80° C. for 18 hours. The mixture wasconcentrated, then dichloromethane (10 mL) and water (10 mL) were added.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was re-dissolved in ethanol (10 mL) and NH₄OH (10 mL, 4.87 mmol)was added. Then the mixture was stirred at room temperature for 2 hours.The mixture was concentrated and purified by prep-TLC (normal phase,silica gel, dichloromethane\methanol=20:1) to give(3-bromo-2-chlorophenyl)methanamine (500 mg, 46% yield) as a yellowsolid. LCMS (ESI) [M+H]⁺=220.0.

Step 2: N-(3-bromo-2-chlorobenzyl)-2,2-diethoxyacetimidamide

Methyl 2,2-diethoxyethanimidate (548 mg, 3.4 mmol) was added dropwise toa stirred solution of (3-bromo-2-chlorophenyl) methanamine (500 mg, 2.27mmol) in methanol (100 mL). The mixture was stirred at room temperaturefor 16 hours. The reaction was concentrated to dryness. The residue wastaken up in dichloromethane and the organic solution was washed withbrine. The organic extract was dried (Na₂SO₄) and concentrated to givethe crude product N-(3-bromo-2-chlorobenzyl)-2,2-diethoxyacetimidamide(500 mg, 1.43 mmol, 63% yield) as a yellow oil, which was used in thenext step without further purification. LCMS (ESI) [M+H]⁺=351.0.

Step 3: 7-bromo-8-chloroisoquinolin-3-amine

The crude N-(3-bromo-2-chlorobenzyl)-2,2-diethoxyacetimidamide (500 mg,1.43 mmol) was placed in a round-bottomed flask at 0° C. under inertatmosphere (N₂) and conc. H₂SO₄ (4207 mg, 42.9 mmol) was added. Thereaction mixture is stirred overnight at room temperature. The reactionmixture was poured into ice water. NH₄OH was added to adjust the pH to8. The solid was collected by filtration to give7-bromo-8-chloroisoquinolin-3-amine (300 mg, 81% yield) as a yellowsolid. LCMS (ESI) [M+H]⁺=257.0.

Example I.6 Intermediate 6: 8-bromo-7-chloroisoquinolin-3-yltrifluoromethanesulfonate

Step 1: (2-bromo-3-chlorophenyl)methanamine

A mixture of 2-bromo-1-chloro-3-methylbenzene (500 mg, 2.43 mmol), NBS(649 mg, 3.65 mmol), benzoyl peroxide (5 mg, 0.02 mmol) and carbontetrachloride (10 mL) was heated at 80° C. for 18 hours. The mixture wasthen concentrated. Dichloromethane (10 mL) and water (10 mL) were thenadded. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in ethanol (10 mL) and NH₄OH (5mL, 2.43 mmol) was added. The mixture was stirred at room temperaturefor 2 hours. The mixture was concentrated and purified by prep-TLC(normal phase, silica gel, dichloromethane\methanol=20:1) to give(2-bromo-3-chlorophenyl)methanamine (300 mg, 1.36 mmol, 55% yield) as ayellow solid. LCMS (ESI) [M+H]⁺=220.0.

Step 2: N-(2-bromo-3-chlorobenzyl)-2,2-diethoxyacetamide

To a mixture of (2,2-diethoxyacetyl)oxysodium (270 mg, 1.59 mmol),(2-bromo-3-chlorophenyl) methanamine (350 mg, 1.59 mmol), HOBT (321 mg,2.38 mmol), EDCI (454 mg, 2.38 mmol) and DMF (50 mL) was added DIPEA(819 mg, 6.35 mmol). The mixture was stirred at room temperature for 18hours. Water (50 mL) was then added. The mixture was extracted withethyl acetate (30 mL×2). The combined organic extracts were washed withwater (50 mL×3) then brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give N-(2-bromo-3-chlorobenzyl)-2,2-diethoxyacetamide(500 mg, 89% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=351.0.

Step 3: 8-bromo-7-chloroisoquinolin-3-ol

A mixture of N-(2-bromo-3-chlorobenzyl)-2,2-diethoxyacetamide (500 mg,1.43 mmol) and conc H₂SO₄ (10 mL, 14.26 mmol) was stirred at roomtemperature for 3 hours. The mixture was poured into ice water. Ammoniumhydroxide was added to adjust the mixture to pH 8. The mixture wasextracted with ethyl acetate (30 mL×2). The organic layer was washedwith water (20 mL×3), brine (20 ml), dried over Na₂SO₄, filtered andconcentrated to give the 8-bromo-7-chloroisoquinolin-3-ol (270 mg, 73%yield) as a yellow solid, which was used in next step without furtherpurification. LCMS (ESI) [M+H]⁺=258.0.

Step 4: 8-bromo-7-chloroisoquinolin-3-yl trifluoromethanesulfonate

A mixture of 8-bromo-7-chloroisoquinolin-3-ol (270 mg, 1.04 mmol),dichloromethane (10 mL) and DIPEA (404 mg, 3.13 mmol) was cooled to 0°C. Triflic anhydride (383.1mg, 1.36 mmol) was added slowly. Then themixture was stirred at room temperature for 16 hours. A saturatedaqueous solution of NH₄Cl (10 mL) was added. The mixture was extractedwith dichloromethane (10 mL×2). The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC (normalphase, silica gel, petroleum ether/ethyl acetate=10/1) to give8-bromo-7-chloroisoquinolin-3-yl trifluoromethanesulfonate (290 mg, 71%yield) as a yellow solid. LCMS (ESI) [M+H]⁺=391.0.

Example I.7 Intermediate 7: 8-bromo-7-fluoroisoquinolin-3-yltrifluoromethanesulfonate

Step 1: (2-bromo-3-fluorophenyl)methanamine

To a solution of 2-bromo-3-fluorobenzonitrile (1.5 g, 7.5 mmol) in THF(10 mL) was added BH₃-THF (2 M in THF, 11.2 mL, 22.4 mmol). Theresulting solution was heated at 60° C. for 2 hours. The mixture wascooled to 0° C. A 1N HCl solution was added to quench the reaction. A 1NNaOH solution was added to adjust the pH of the mixture to 8. Themixture was extracted with dichloromethane (20 mL×2). The organicextracts were washed with water (20 mL×3), brine (20 ml), dried overNa₂SO₄, filtered and concentrated to give(2-bromo-3-fluorophenyl)methanamine (850 mg, 56% yield) as a yellowsolid. LCMS (ESI) [M+H]⁺=206.0.

Step 2: N-(2-bromo-3-fluorobenzyl)-2,2-diethoxyacetamide

A mixture of (2,2-diethoxyacetyl)oxysodium (667 mg, 3.92 mmol),(2-bromo-3-fluorophenyl)methanamine (800 mg, 3.92 mmol), HOBT (793 mg,5.88 mmol) and DIPEA (2.0 g, 15.68 mmol) in DMF (5 mL) was stirred atroom temperature for 18 hours. Water (50 mL) was then added. The mixturewas extracted with ethyl acetate (30 mL×2). The organic layer was washedwith water (50 mL×3), brine (20 ml), dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatography(petroleum ether/ethyl acetate=5/1) to giveN-(2-bromo-3-fluorobenzyl)-2,2-diethoxyacetamide (820 mg, 62% yield) asa colorless oil. LCMS (ESI) [M+H]⁺=336.0.

Step 3: 8-bromo-7-fluoroisoquinolin-3-ol

A mixture of N-(2-bromo-3-fluorobenzyl)-2,2-diethoxyacetamide (953 mg,2.85 mmol) and cone H₂SO₄ (10 mL, 28 mmol) was stirred at roomtemperature for 3 hours. The mixture was poured into ice water. Ammoniumhydroxide was added to adjust the pH to 8. The mixture was extractedwith ethyl acetate (30 mL×2). The organic layer was washed with water(20 mL×3), brine (20 mL), dried over Na₂SO₄, filtered and concentratedto get crude 8-bromo-7-fluoroisoquinolin-3-ol (500 mg, 72% yield) as ayellow solid, which was used in next step without further purification.LCMS (ESI) [M+H]⁺=243.9.

Step 4: 8-bromo-7-fluoroisoquinolin-3-yl trifluoromethanesulfonate

A mixture of 8-bromo-7-fluoroisoquinolin-3-ol (500 mg, 2.07 mmol),dichloromethane (10 mL) and DIPEA (799 mg, 6.2 mmol) was cooled to 0° C.Triflic anhydride (757 mg, 2.69 mmol) was added slowly. The mixture wasstirred at room temperature for 3 hours. Aqueous saturated NH₄Cl (10 mL)was added. The mixture was extracted with dichloromethane (10 mL×2). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (normal phase silicagel, petroleum ether/ethyl acetate=10/1) to give8-bromo-7-fluoroisoquinolin-3-yl trifluoromethanesulfonate (600 mg, 77%yield) as a yellow solid. LCMS (ESI) [M+H]⁺=373.9.

Example I.8 Intermediate 8:(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

Step 1: 7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine

A mixture of 7-bromo-8-chloro-6-iodo-isoquinolin-3-amine (3.6 g, 9.39mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(2.5 g, 11.41 mmol), Pd(PPh₃)₄ (750 mg, 0.65 mmol), K₂CO₃ (3.8 g, 27.54mmol) in 1,4-dioxane (160 mL) and water (40 mL) was stirred at 70° C.under Ar for 23 hours. The reaction mixture was cooled to roomtemperature. Ethyl acetate was added and the mixture was washed withbrine (100 mL). The organic layer was separated, dried over Na₂SO₄,filtered and evaporated. The residue was purified with silica-gel columnchromatography (petroleum ether/ethyl acetate=1:2 to ethyl acetate) togive 7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (2.9 g,89% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=348.0.

Step 2:(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

Oxalyl chloride (3.0 g, 23.62 mmol) was added dropwise to a suspensionof (±)-trans-2-cyanocyclopropanecarboxylic acid (1.2 g, 10.8 mmol) at 0°C. The mixture was stirred at 0° C. for 1 hour. The mixture wasevaporated at room temperature to remove the dichloromethane and excessoxalyl chloride. The residue was re-suspended in dichloromethane (5 mL)and was added dropwise to a mixture of7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (2.9 g, 8.32mmol), and pyridine (10 mL, 123.64 mmol) in dichloromethane (50 mL) at0° C. Then the reaction mixture was stirred at 0° C. for 0.5 hours. Thereaction mixture was diluted with dichloromethane (100 mL) and washedwith H₂O (50 mL). The organic layer was separated, dried over Na₂SO₄,filtered and evaporated. The residue was purified with silica-gel columnchromatography (petroleum ether/ethyl acetate=1:1 to 1:2) to give(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(2.85 g, 78% yield) as a light brown solid. LCMS (ESI) [M+H]⁺=441.0.

Example I.9 Intermediate 9: (3-amino-8-chloro-6-isoquinolyl)boronic acid

A mixture of bis(pinacolato)diboron (976 mg, 3.84 mmol),6-bromo-8-chloro-isoquinolin-3-amine (900 mg, 3.5 mmol), Pd(dppf)Cl₂(127 mg, 0.17 mmol) and potassium acetate (1370 mg, 13.98 mmol) in1,4-dioxane (20 mL) was stirred at 100° C. for 3 hours under nitrogen.Ethyl acetate (50 mL) was added. The mixture was filtered andconcentrated to give crude (3-amino-8-chloro-6-isoquinolyl)boronic acid(830 mg, 78% yield) as a yellow oil, which was used directly withoutfurther purification. LCMS (ESI): [M+H]⁺=223.1.

Example I.10 Intermediate 10:(±)-trans-N-(6-bromo-8-chloroisoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of ethanedioyl dichloride (1330 mg, 10.49 mmol),(±)-trans-2-cyanocyclopropanecarboxylic acid (582 mg, 5.24 mmol) and onedrop of DMF in dichloromethane (5 mL) was stirred at room temperaturefor 0.5 hours. The reaction was concentrated to dryness. To a solutionof 6-bromo-8-chloro-isoquinolin-3-amine (450 mg, 1.75 mmol) indichloromethane (5 mL) and pyridine (1 mL) was added the residue inportions at 0° C. The mixture was stirred for 1 hour at roomtemperature. The reaction was concentrated to dryness. The residue waspurified by silica-gel column chromatography (petroleum ether/ethylacetate=4:1 to petroleum ether:ethyl acetate=2:1) to give the titlecompound as a yellow solid (200 mg, 32.6% yield). LCMS (ESI)[M+H]⁺=352.0.

Example I.11 Intermediate 11:(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide

Step 1: (±)-cis-2-fluorocyclopropanecarbonyl chloride

To a solution of (±)-cis-2-fluorocyclopropanecarboxylic acid (2.1 g,20.18 mmol) in dichloromethane (10 mL) and DMF (0.10 mL) was addeddropwise ethanedioyl dichloride (3.33 g, 26.23 mmol). The mixture wasstirred at 25° C. for 2 hours. The reaction mixture was concentrated invacuum to give a yellow residue, which was then used directly in thenext step.

Step 2:(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide

To a solution of 6-bromo-8-chloro-isoquinolin-3-amine (2.0 g, 7.77 mmol)in dichloromethane (10 mL) and pyridine (1.88 mL, 23.3 mmol) was added asolution of (±)-cis-2-fluorocyclopropanecarbonyl chloride (2.38 g, 19.42mmol) dissolved in dichloromethane (2 mL). The mixture was stirred at25° C. for 2 hours and then concentrated. Water (10 mL) was added andthen a 1 N HCl solution was added to adjust the pH of the mixture to 6.The mixture was extracted with dichloromethane (10 mL×3). The organiclayer was washed with brine (20 ml), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography(petroleum ether/ethyl acetate=4:1) to give(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(2.3 g, 86% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=343.0.

Example I.12 Intermediate 12:(±)-trans-8-chloro-3-((trans)-2-cyanocyclopropanecarboxamido)isoquinolin-6-ylboronicacid

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(300 mg, 0.86 mmol), bis(pinacolato)diboron (261 mg, 1.03 mmol),potassium acetate (210 mg, 2.14 mmol) and Pd(dppf)Cl₂ (31 mg, 0.04 mmol)in 1,4-dioxane (4 mL) was stirred in a sealed tube at 80° C. for 3hours. The mixture was concentrated to give(±)-[8-chloro-3-[[(trans)-2-cyanocyclopropane carbonyl]amino]-6-isoquinolyl]boronic acid (240 mg, 59% yield) as a black solid.LCMS (ESI): [M+H]⁺=316.0.

Examples I.13 Intermediate 13: tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (3.6 g, 11.2mmol), tert-butylN-tert-butoxycarbonyl-N-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]carbamate(10 g, 23 mmol), Pd(dppf)Cl₂ (0.82 g, 1.1 mmol), potassium carbonate(3.4 g, 25 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was stirredat 90° C. for 2 h. The reaction was filtered. The product was extractedwith ethyl acetate. The combined organic extracts were combined andconcentrated under vacuum. The residue was purified by flashchromatrography (40% ethyl acetate in pet. ether) to give the titlecompound as a yellow oil (3.4 g, 61%).

Examples I.14 Intermediate 14: tert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

Step 1: tert-butyl7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

To a solution of7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (1 g, 4.37mmol) in tetrahydrofuran (2 mL) was added dropwise LiHMDS (8.73 mL, 8.73mmol, 1 mol/L) at 0° C. The resulting solution was stirred undernitrogen for 0.5 h at 0° C. Then di-tert-butyl dicarbonate (2.85 g,13.07 mmol) was added and the reaction was stirred at room temperaturefor 2 h. The reaction was quenched by methanol (50 mL). The solvent wasconcentrated under vacuum. The residue was purified by silica gel flashchromatography (ethyl acetate/petroleum ether, 1/4) to afford tert-butyl7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (800mg, 2.43 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=329.2.

Step 2: tert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A mixture of tert-butyl7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (6.2g, 18.83 mmol), dipinacoldiboron (23.93 g, 94.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.76 g,3.77 mmol) and potassium acetate (5.55 g, 56.62 mmol) in 1,4-dioxane (2mL) was stirred under nitrogen for 2.5 h at 90° C. The solvent wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(30%) to afford tert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(5 g, 13.29 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=376.3.

Examples 1.15 Intermediate 15:2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid

Step 1: Diphenyl(propyl)sulfonium tetrafluoroborate

To a solution of silver tetrafluoroborate (2 g, 10.31 mmol) indichloromethane (20 mL) was added 1-iodopropane (1.75 g, 10.31 mmol) anddiphenyl sulfide (5.76 g, 30.93 mmol) at 0° C. The reaction was stirredat 35° C. for 15 hours. The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was washed withdichloromethane-ether to afford diphenyl(propyl)sulfoniumtetrafluoroborate (2 g, 6.32 mmol) as a white solid. LCMS (ESI)[M+H]⁺=229.

Step 2: tert-butyl2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

To a solution of diphenyl(propyl)sulfonium tetrafluoroborate (1.50 g,4.75 mmol) in 1,2-dimethoxyethane (30 mL) and dichloromethane (3 mL) wasadded lithium diisopropylamide (5.54 ml, 11.09 mmol) at −78° C. Theresulting mixture was stirred for 1 hour at −78° C. Then tert-butyl(Z)-3-(1-methylpyrazol-4-yl)prop-2-enoate (330 mg, 1.58 mmol) was addedand stirred at −78° C. to 25° C. for 15 hours. The reaction was quenchedwith water. The resulting mixture was extracted with dichloromethane anddried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford tert-butyl2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (350 mg, 1.40mmol) as a brown oil. LCMS (ESI) [M+H]⁺=251.

Step 3: 2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid

A solution of trans-tert-butyl2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (350 mg, 1.4mmol) and 2,2,2-trifluoroacetic acid (8 mL) in dichloromethane (3 mL)was stirred at 25° C. for 1 hour.The mixture was concentrated undervacuum. The resulting residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% HCl in water) to afford2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid (260 mg,1.34 mmol) as a brown oil. Product mixture consists of 4 stereoisomerswhere pyrazole is trans to carboxylic acid and(+/−)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylicacid as a contaminant. LCMS (ESI) [M+H]⁺=195.

Examples I.16 Intermediate 16:2-bromo-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

Step 1: 2-(3,5-dibromopyrazol-1-yl)acetonitrile

A mixture of 3,5-dibromo-1H-pyrazole (1.0 g, 4.43 mmol) and potassiumcarbonate (1.22 g, 8.85 mmol) in N,N-dimethylformamide (20 mL) wasstirred at 25° C. for 10 min. Bromoacetonitrile (796.59 mg, 6.64 mmol)was added and the reaction was stirred at 25° C. for 2 h. Afterfiltration, the filtrate was diluted with ethyl acetate (30 mL). Thereaction was washed with water. The organic phase was dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleumether/dichloromethanol (1/1) to afford2-(3,5-dibromopyrazol-1-yl)acetonitrile (950 mg, 3.59 mmol) as a whitesolid. LCMS (ESI) [M+H]⁺=264.

Step 2: 2-[3-bromo-5-(2-methylprop-1-enyl)pyrazol-1-yl]acetonitrile

A mixture of 2-(3,5-dibromopyrazol-1-yl)acetonitrile (1.0 g, 3.77 mmol),4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane(687.29 mg, 3.77 mmol), Pd(dppf)Cl₂ (552.64 mg, 0.75 mmol), andpotassium carbonate (1.56 g, 11.32 mmol) in 1,4-dioxane (20 mL) andwater (2 mL) was stirred under nitrogen for 1 h at 100° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/3) to afford2-[3-bromo-5-(2-methylprop-1-enyl)pyrazol-1-yl]acetonitrile (700 mg,2.92 mmol) as a white solid. LCMS (ESI) [M+H]⁺=240.

Step 3:2-bromo-5,5-dimethyl-6,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of 2-[3-bromo-5-(2-methylprop-1-enyl)pyrazol-1-yl]acetonitrile(700 mg, 2.92 mmol) in methylsulfonic acid (15 mL) was stirred at 65° C.for 3 d. The reaction was quenched with ice water. The reaction mixturewas adjusted to pH 9-10 with an aqueous sodium hydroxide solution. Theresulting solution was extracted with dichloromethane and dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% NH₄HCO₃ in water) to afford2-bromo-5,5-dimethyl-6,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(300 mg, 1.16 mmol) as a white solid. LCMS (ESI) [M+H]⁺=258.

Step 4:2-bromo-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-bromo-5,5-dimethyl-6,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(100 mg, 0.39 mmol) and potassium tert-butoxide (52.07 mg, 0.46 mmol) intetrahydrofuran (10 mL) was stirred at 25° C. for 10 min. lodomethane(82.52 mg, 0.58 mmol) was added. The reaction was stirred at 25° C. for1 h. The reaction was concentrated under vacuum and purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5) to afford2-bromo-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(80 mg, 0.29 mmol) as a white solid. LCMS (ESI) [M+H]⁺=272.

Examples I.17 Intermediate 17:2-bromo-4-methylene-5,6-dihydro-4H-pyrazol[1,5-d][1,4]diazepin-7(8H)-one

Step 1: 3,5-dibromo-1H-pyrazole

To a 3 L 3-necked round-bottom flask was added compound 1 (200 g, 656mmol, 1.0 eq) in dimethyl tetrahydrofuran (1000 mL) under N₂ and thenthe solution was cooled to −78° C. n-BuLi (2.5 M, 525 mL, 2.0 eq) wasadded dropwise to the above solution for 1 hour at −78° C. and themixture was stirred at −78° C. for 3 hours. TLC (Petroleum ether/Ethylacetate=3/1, R_(f)=0.51) showed the reaction was completed and one mainnew spot formed. The two reactions were combined and the reactionmixture was poured into water (1000 mL) at 0° C. and the pH value of thesolution was acidified to 4-5 with 2N HCl. The resulting solution wasextracted with ethyl acetate (1000 mL, 800 mL, 400 mL). The combinedorganic phase was washed with brine (800 mL), dried with anhydrousNa₂SO₄ and concentrated under vacuum to give the title compound (284 g,1.26 mol, 95.8% yield) as a yellow solid. The crude product was directlyused to the next step without further purification.

Step 2: tert-butyl 2-(3,5-dibromo-1H-pyrazol-1-yl)acetate

To the solution of 3,5-dibromo-1H-pyrazole (137 g, 607 mmol, 1.0 eq) inMeCN (959 mL) was added tert-butyl 2-chloroacetate (137 g, 910 mmol, 131mL, 1.5 eq), K₂CO₃ (137 g, 989 mmol, 1.63 eq) and TBAI (11.0 g, 29.7mmol, 0.049 eq). The resulting solution was stirred at 25° C. for 12hours. TLC (Petroleum ether/Ethyl acetate=5/1, R_(f)=0.74) showed thereaction was complete and one main new spot formed. The reaction mixturewas filtered, the filter cake was washed with EtOAc (500 mL×3, 300 mL,200 mL). The combined filtrate was concentrated to give a residue. Theresidue was dissolved in EtOAc (2.0 L), washed with water (1.0 L), brine(1.0 L). The organic phase was dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to give the title compound (744 g, crude) as abrown oil. ¹H NMR: (400 MHz, CDCl₃): δ 6.35 (s, 1H), 4.80 (s, 2H), 1.46(s, 9H).

Step 3: 2-(3,5-dibromo-1H-pyrazol-1-yl)acetic acid

To the solution of compound tert-butyl2-(3,5-dibromo-1H-pyrazol-1-yl)acetate (248 g, 729 mmol, 1.0 eq) in DCM(140 mL) was added TFA (2.08 kg, 18.2 mol, 1.35 L, 25 eq) and theresulting solution was heated to 80° C. and stirred for 2 hours. TLC(Petroleum ether/Ethyl acetate=5/1, R_(f)=0.03) showed the reaction wascomplete and one main new spot formed. The reaction was repeated twice.The combined reaction mixtures were concentrated under reduced pressureto give a crude product. The crude product was diluted with petroleumether/ethyl acetate (4/1, 1.0 L) and the resulting suspension wasstirred at 25° C. for 1 hour, then filtered. The filter cake wascollected and dried in vacuum to give the title compound (471 g, 1.66mol, 75.8% yield) as a creamy white solid. ¹H NMR: (400 MHz, DMSO) δ13.3 (br s, 1H), 6.70 (s, 1H), 4.96 (s, 2H).

Step 4: N-allyl-2-(3,5-dibromo-1H-pyrazol-1-yl)acetamide

To the solution of 2-(3,5-dibromo-1H-pyrazol-1-yl)acetic acid (157 g,553 mmol, 1.0 eq) in DMF (1.10 L) was added DIPEA (357 g, 2.77 mol, 482mL, 5.0 eq) and EDCI (138 g, 719 mmol, 1.3 eq) at 0° C., the resultingsolution was stirred at 0° C. for 30 min. Then HOBt (97.1 g, 719 mmol,1.3 eq) was added and the mixture was stirred at 0° C. for another 30min. Then prop-2-en-1-amine (47.4 g, 830 mmol, 62.2 mL, 1.5 eq) wasadded at 0° C. and the mixture was warmed to 25° C. and stirred for 16hours. TLC (Petroleum ether/Ethyl acetate=1/1, R_(f)=0.60) showed thereaction was completed and one main new spot formed. The reaction wasrepeated two more times. The three batches of reactions were combinedand the reaction mixture was poured into ice water (12.0 L), extractedwith ethyl acetate (2.00 L, 2.00 L, 1.00 L). The combined organic phasewas washed with brine (2.0 L), and then concentrated in vacuum to give acrude product. The crude product was purified by column chromatographyon silica gel (Petroleum ether/Ethyl acetate=3/1) to afford the titlecompound (340 g, 1.05 mol, 63.5% yield) as a white solid. ¹H NMR:(400MHz, CDCl₃) δ 6.41 (s, 1H), 5.89 (br s, 1H), 5.79 (m, 1H), 5.08-5.17(m, 2H), 4.85 (s, 2H), 3.86-3.93 (m, 2H).

Step 5:N-allyl-2-(3,5-dibromo-1H-pyrazol-1-yl)-N-(4-methoxybenzyl)acetamide

To a solution of N-allyl-2-(3,5-dibromo-1H-pyrazol-1-yl)acetamide (103g, 319 mmol, 1.0 eq) in THF (721 mL) was added KOH (32.2 g, 574 mmol,1.8 eq), 18-Crown-6 (3.37 g, 12.8 mmol, 0.04 eq) and1-(chloromethyl)-4-methoxy-benzene (64.9 g, 415 mmol, 56.5 mL, 1.3 eq),then the mixture was stirred at 25° C. for 64 h. TLC (Petroleumether/Ethyl acetate=2/1, R_(f)=0.50) showed one main new spot formed.The reaction was repeated two more times. The three batches reactionswere combined and the reaction mixture was added water (1.00 L), and thepH value was adjusted to 7-8 with 1M HCl, then extracted with EtOAc(1.00 L, 800 mL×3). The combined organic phase was washed with brine(800 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to give a crude product. The crude product was purified by columnchromatography on silica gel (Petroleum ether/Ethyl acetate=2/1) toafford the title compound (320 g, 722 mmol, 75.5% yield) as a yellowoil.

Step 6:2-bromo-6-(4-methoxybenzyl)-4-methylene-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

To a solution ofN-allyl-2-(3,5-dibromo-1H-pyrazol-1-yl)-N-(4-methoxybenzyl)acetamide(50.0 g, 113 mmol, 1.0 eq) in DMF (1.0 L) was added K₂CO₃ (31.2 g, 226mmol, 2.0 eq), Pd(PPh₃)₄ (17.0 g, 14.7 mmol, 0.13 eq) under Ar, then themixture was stirred at 120° C. for 16 hours. The reaction was repeatedsix more times. The seven batches of reactions were combined and thereaction mixture was concentrated in vacuum to remove the solvent togive a residue. Then the residue was added water (2.0 L), extracted withethyl acetate (2.0 L, 1.0 L, 1.0 L). The combined organic phase waswashed with brine (1.0 L) and concentrated to give a crude product. Thecrude product was purified by column chromatography on silica gel(Petroleum ether/Ethyl acetate=2/1) to afford the title compoundcompound (74.1 g, 204 mmol, 25.9% yield, 98.7% purity) as a white solid.¹H NMR: (400MHz, CDCl₃) δ 7.21 (d, J=8.8 Hz, 2H), 6.86-6.92 (m, 2H),6.52 (s, 1H), 5.50 (s, 1H), 5.20 (s, 2H), 5.02 (s, 1H), 4.58 (s, 2H),4.13 (s, 2H), 3.83 (s, 3H).

Step 7:2-bromo-4-methylene-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of2-bromo-6-(4-methoxybenzyl)-4-methylene-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(3.90 g, 10.8 mmol, 1.0 eq), TFA (38.4 g, 336 mmol, 24.9 mL, 31.3 eq)and trifluoromethanesulfonic acid (16.2 g, 108 mmol, 9.5 mL, 10 eq) inDCM (28 mL) was stirred at 25° C. for 12 hours. The reaction mixture wasconcentrated to give a residue. To the residue was added water (100 mL),then the pH value was adjusted to 6-7 with saturated aqueous NaHCO₃solution, extracted with EtOAc (100 mL×3, 60 mL×3). The combined organicphase was dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to give a crude product. The crude product was purified by columnchromatography on silica gel (Petroleum ether/Ethyl acetate=1/1) toafford the title compound (1.90 g, 7.85 mmol, 72.9% yield) as a graysolid. ¹H NMR: (400MHz, CDCl₃) δ 6.88 (s, 1H), 6.54 (s, 1H), 5.55 (s,1H), 5.21 (s, 1H), 5.08 (s, 2H), 4.15 (d, J=6.0 Hz, 2H).

Examples I.18 Intermediate 18:2-Bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

Step 1:2-(3,5-Dibromo-1H-pyrazol-1-yl)-N-methyl-N-(prop-2-en-1-yl)acetamide

A solution of 2-(3,5-dibromo-1H-pyrazol-1-yl)acetic acid (15 g, 52.84mmol), methyl(prop-2-en-1-yl)amine (5.7 g, 80.15 mmol),N,N-diisopropylethylamine (27 g, 208.9 mmol) and HATU (30 g, 78.9 mmol)in N,N-dimethylformamide (500 mL) was stirred for 16 hours at roomtemperature. The resulting mixture was diluted with ethyl acetate andthen washed with sodium chloride solution. The organic phase was driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(2/3) to afford2-(3,5-dibromo-1H-pyrazol-1-yl)-N-methyl-N-(prop-2-en-1-yl)acetamide(16.3 g, 92%) as a yellow oil. LCMS (ESI) [M+H]⁺=338.0.

Step 2:2-Bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-(3,5-dibromo-1H-pyrazol-1-yl)-N-methyl-N-(prop-2-en-1-yl)acetamide (5g, 14.84 mmol), palladium acetate (166 mg, 0.74 mmol),triphenylphosphine (388 mg, 1.48 mmol), TBAB (4.8 g, 14.890 mmol) andpotassium acetate (4.2 g, 42.80 mmol) in N,N-dimethylformamide (100 mL)was stirred for 10 h at 80° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (2/1) to afford2-bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(3.2 g, 84%) as a brown oil. LCMS (ESI) [M+H]⁺=258.1.

Examples I.19 Intermediate 19:2-bromo-6-isopropyl-4-methylene-5,6-dihydro-4H-pyrazol[1,5-d][1,4]diazepin-7(8H)-one

To a mixture ofN-allyl-2-(3,5-dibromopyrazol-1-yl)-N-isopropyl-acetamide (6.3 g, 17.26mmol), palladium diacetate (386.5 mg, 1.73 mmol), triphenylphosphine(904.29 mg, 3.45 mmol) and tetrabutylammonium bromide (5.56 g, 17.26mmol) in N,N-dimethylformamide (150 mL) was added potassium acetate(4.87 g, 51.77 mmol) at 25° C. The resulting mixture was stirred for 12hours at 90° C. The reaction mixture was diluted with ethyl acetate andthen washed with water. The organic layer was dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (2/3) to afford2-bromo-6-isopropyl-4-methylene-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(2.34 g, 8.23 mmol, 47.7% yield) as a yellow solid. LCMS (ESI)[M+H]⁺=284.

Examples I.20 Intermediate 20:2′-bromo-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one

A mixture of trimethylsulfoxonium iodide (1.29 g, 5.86 mmol) andpotassium tert-butoxide (656 mg, 5.85 mmol) in dimethyl sulfoxide (30mL) was stirred for 30 min at room temperature. Then a solution of2-bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(500 mg, 1.95 mmol) in dimethyl sulfoxide (3 mL) was added. The mixturewas then stirred for 12 h at 50° C. The reaction mixture was dilutedwith ethyl acetate and then washed with water. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by silica gel column withdichloromethane/methanol (10/1) to afford2′-bromo-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one(120 mg, 23%) as a white solid. LCMS (ESI) [M+H]⁺=270.

Examples I.21 Intermediate 21:2-bromo-6-methyl-5,6-dihydro-4H-pyrazol[1,5-d][1,4]diazepin-7(8H)-one

Step 1: Methyl 2-(3-bromo-5-methyl-pyrazol-1-yl)acetate

A solution of 3-bromo-5-methyl-1H-pyrazole (100 g, 621.12 mmol) , methyl2-chloroacetate (101.11 g, 931.68 mmol) and K₂CO₃ (154.29g, 1118 mmol)in N,N-dimethylformamide (1 L) was added TBAI (11.46 g, 31.06 mmol). Theresulting solution was stirred for 12 h at 20° C. The reaction mixturewas diluted with EA (5000 mL). The solution was washed with water (300mL×3) and the organic layers were combined. The organic layer was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting with PE/DCM(60/40) to afford methyl 2-(3-bromo-5-methyl-pyrazol-1-yl)acetate (120g,82.9% yield) as a white solid.

Step 2: Methyl 2-[3-bromo-5-(bromomethyl)pyrazol-1-yl]acetate

A solution of methyl 2-(3-bromo-5-methyl-pyrazol-1-yl)acetate (50.0 g,214.54 mmol) and AIBN (3.52 g, 21.45 mmol) in carbon tetrachloride (1500mL) was stirred at RT for 5 mins. 1-Bromo-2,5-pyrrolidinedione (40.09 g,225.26 mmol) was added. The mixture was stirred at 80° C. for 1 hour.The reaction mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with PE/EA (92/8)to afford methyl 2-[3-bromo-5-(bromomethyl)pyrazol-1-yl]acetate (35.5 g,53% yield) as a white solid.

Step 3: Methyl 2-(3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl)acetate

A solution of methyl 2-[3-bromo-5-(bromomethyl)pyrazol-1-yl]acetate(35.4 g, 113.48 mmol) and sodium cyanide (8.87 g, 181.02 mmol) indimethyl sulfoxide (550 mL) was stirred at RT for 1 hour. The reactionsolution was diluted with EA (2.5 L). The solution was washed with water(200 mL×5) and the organic layers were combined. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with DCM/MeOH (99/1) to afford methyl2-(3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl)acetate (17.6 g, 60% yield)as a white solid.

Step 4: Methyl 2-(5-(2-aminoethyl)-3-bromo-1H-pyrazol-1-yl)acetate

To a solution of methyl 2-[3-bromo-5-(cyanomethyl)pyrazol-1-yl]acetate(3.0 g, 11.62 mmol) in methanol (600 mL) was added PtO₂ (600 mg, 2.64mmol). The mixture was stirred under 10 atm of hydrogen gas at 25° C.for 15 hours. The mixture was filtrated. The filtrate would be directlyused in the next step without purification.

Step 5: 2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one

To a solution (600 mL) of methyl2-[5-(2-aminoethyl)-3-bromo-pyrazol-1-yl]acetate was added TEA (70 mL).The mixture was stirred at 25° C. for 15 hours. The resulting solutionwas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with DCM/MeOH (98/2) to afford2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (1.12 g,41.9% yield in two steps) as a white solid.

Step 6:2-bromo-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

To a mixture of2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine (469.53 mg,2.17 mmol) and potassium tert-butoxide (365.74 mg, 3.26 mmol) intetrahydrofuran (20mL) was added iodomethane (616.86 mg, 4.35 mmol) at20° C. The resulting solution was stirred at 20° C. for 1 h. The mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(20/1) to afford2-bromo-6-methyl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine (400mg, 1.74 mmol, 80% yield). LCMS (ESI) [M+H]⁺=244

Examples I.22 Intermediate 22:2-bromo-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (3.0 g,13.04 mmol) and NaH (1.56 g, 39.12 mmol) in N,N-dimethylformamide (75mL) was stirred at 0° C. for 10 min. Then 2-iodopropane (11.08 g, 65.2mmol) was added. The mixture was stirred at 25° C. for 1 hour. Thereaction was quenched with water. The mixture was concentrated undervacuum. The resulting residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% NH₄HCO₃ in water) to afford2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(2.1 g, 7.7166 mmol, 59.2% yield) as a white solid. LCMS (ESI)[M+H]⁺=272.

Examples I.23 Intermediate 23:8-bromo-5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepine

Step 1: 2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-7-thione

A mixture of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (314 mg,1.36 mmol) and Lawsson reagent (551.4 mg, 1.36 mmol) in 1,4-dioxane (10mL) was stirred at 90° C. for 1 h. The reaction was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (96/4) to afford2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-7-thione (265mg, 78.9%) as a white solid. LCMS (ESI) [M+H]⁺=246.0.

Step 2:2-bromo-N-(2,2-diethoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-amine

A mixture of2-bromo-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-7(8H)-thione (265.0mg, 1.07 mmol), 2,2-diethoxyethan-1-amine(1.42 g, 10.7 mmol) and silvercarbonate (590 mg, 2.14 mmol) in tetrahydrofuran (10 mL) was stirred at80° C. for 1 h. The solvent was concentrated under vacuum. The residuewas purified by reverse-phase column eluting with water (0.05%TFA)/CH₃CN (85/15) to afford2-bromo-N-(2,2-diethoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-amine(295 mg, 80%) as a brown oil. LCMS (ESI) [M+H]⁺=345.0.

Step 3:8-bromo-5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepine

A solution of2-bromo-N-(2,2-diethoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-amine(228 mg, 0.66 mmol) and concentrated hydrochloric acid (0.17 mL, 0.66mmol) in acetic acid (5 mL) was stirred at 80° C. for 1 h. The reactionwas concentrated under vacuum. The residue was purified by reverse-phasecolumn eluting with water (0.05% TFA)/ACN (85/15) to afford8-bromo-5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepine (150mg, 89.7%) as a brown oil. LCMS (ESI) [M+H]⁺=253.0.

Exemplary Compounds Example 1(±)-trans-N-[8-amino-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 1)

Step 1:(±)-trans-N-[8-chloro-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(350 mg, 1.0 mmol), 2-methyl-4-cyanophenylboronic acid (193 mg, 1.2mmol), Pd(PPh₃)₄ (115 mg, 0.1 mmol) and Na₂CO₃ (212 mg, 2 mmol) in1,4-dioxane (15 mL) and water (1 mL) under Ar was stirred at 90° C. for3 hours. The mixture was concentrated and purified by columnchromatography (ethyl acetate/hexane=1:3) to afford(±)-trans-N-[8-chloro-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(380 mg, 86% yield) as a white solid. LCMS (ESI) [M+H]⁺=387.1.

Step 2:(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.26 mmol), benzophenone imine (94 mg, 0.52 mmol), Pd(OAc)₂ (12mg, 0.05 mmol), Xantphos (60 mg, 0.1 mmol) and Cs₂CO₃ (168 mg, 0.52mmol) in DMF (6 mL) and toluene (6 mL) was stirred under Ar at 130° C.for 2.5 hours. Ethyl acetate (20 mL) was added. The mixture was washedwith brine (3×50 mL), dried with Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by column chromatography(ethyl acetate/hexane=1:3) to afford(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(130 mg, 74% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=532.1.

Step 3:(±)-trans-N-[8-amino-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixtureof(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(130 mg, 0.19 mmol) in dichloromethane (10 mL), water (1 mL) and2,2,2-trifluoroacetic acid (2 mL) was stirred at 25° C. for 1 hour. Thereaction mixture was neutralized with NH₄OH (37% yield) to pH=7-8. Themixture was concentrated and purified by column chromatography (ethylacetate/hexane=1:2) to afford(±)-trans-N-[8-amino-6-(4-cyano-2-methyl-phenyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(65 mg, 93% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.842,[M+H]⁺=368.1, method=C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 9.35(s, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.44 (d,J=8.0 Hz, 1H), 6.88 (s, 1H), 6.54 (d, J=1.2 Hz, 1H), 6.39 (s, 2H),2.78-2.73 (m, 1H), 2.29 (s, 3H), 2.16-2.11 (m, 1H), 1.62-1.57 (m, 1H),1.45-1.44 (m, 1H).

Example 2N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(Compound 2)

Step 1:N-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]cyclopropanecarboxamide

A mixture of N-(6-bromo-8-chloro-3-isoquinolyl)cyclopropanecarboxamide(270 mg, 0.83 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500mg, 0.91 mmol), Pd(dppf)Cl₂ (121 mg, 0.17 mmol) and Na₂CO₃ (175 mg, 1.66mmol) in 1,4-dioxane (5 mL) was heated in a glove box at 90° C. for 18hours. The reaction was concentrated and purified by prep-TLC (petroleumether:ethyl acetate=2:1) to giveN-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]cyclopropanecarboxamide(240 mg, 72% yield) as a white solid. LCMS (ESI) [M+H]⁺=338.0

Step 2:N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture ofN-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]cyclopropanecarboxamide(120 mg, 0.36 mmol), benzophenone imine (77 mg, 0.43 mmol), Cs₂CO₃ (347mg, 1.07 mmol), Pd(OAc)₂ (16 mg, 0.07 mmol) and XantPhos (41 mg, 0.07mmol) in DMF (3 mL) and toluene (3 mL) was heated in a microwave at 150°C. for 3 hours. The mixture was filtered and concentrated. THF (5 mL)and HCl in 1,4-dioxane (4 M, 3 mL, 12 mmol) was added, followed bystirring at room temperature for 30 minutes. The mixture was filteredand concentrated. The crude product was purified by prep-HPLC to affordN-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]cyclopropane-carboxamide(21 mg, 18.6% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.781,[M+H]⁺=319.2, method=C; ¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H),9.31(s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.34(d, J=4.8 Hz, 1H), 6.88 (s, 1H), 6.54 (s, 1H), 6.33 (s, 2H), 2.29 (s,3H), 2.07-2.04 (m, 1H), 0.83-0.80 (m, 4H).

Example 3:(±)-cis-N-[8-amino-6-[4-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 3)

Step 1:(±)-cis-N-[8-chloro-6-[4-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(170 mg, 0.49 mmol), 1-hydroxy-3H-oxaborolo[3,4-c]pyridine (1 g, 7.41mmol), PdCl₂dppf (150 mg, 0.21 mmol), K₂CO₃ (200 mg, 1.45 mmol) in1,4-dioxane (16 mL) and water (4 mL) was stirred under Ar at 80° C. for1 hour. The reaction mixture was cooled to room temperature, dilutedwith ethyl acetate (100 mL), and washed with brine (20 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by silica-gel column chromatography (petroleumether/ethyl acetate=1:2) to afford(±)-cis-N-[8-chloro-6-[4-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(140 mg, 77% yield) as a light brown solid. LCMS (ESI) [M+H]⁺=372.0.

Step 2:(±)-cis-N-[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-8-chloro-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-[4-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(140 mg, 0.38 mmol), tert-butyldimethylchlorosilane (500 mg, 3.32 mmol),triethylamine (600 mg, 5.94 mmol) in dichloromethane (15 mL) wasrefluxed overnight. The reaction mixture was concentrated and theresulting residue was purified with silica-gel column chromatography(petroleum ether/EA=2:1 to 1:1) to afford(±)-cis-N-[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-8-chloro-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(110 mg, 59% yield) as a light brown solid. LCMS (ESI) [M+H]⁺=486.2.

Step 3: (±)-tert-butylN-[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-8-isoquinolyl]carbamate

A mixture of(±)-cis-N-[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-8-chloro-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(95 mg, 0.20 mmol), BocNH₂ (300 mg, 2.56 mmol), Pd₂dba₃ (40 mg, 0.04mmol), BrettPhos (40 mg, 0.07 mmol), t-BuONa (40 mg, 0.42 mmol) in1,4-dioxane (10 mL) was stirred under Ar at 90° C. for 1 hour. Thereaction mixture was cooled to room temperature, diluted with ethylacetate (100 mL), and washed with sat. NH₄Cl (20 mL). Organic layer wasseparated, dried over Na₂SO₄, filtered and evaporated. The residue waspurified by silica-gel column chromatography (petroleum ether/ethylacetate=1:1 to 1:2) to afford (±)-tert-butylN-[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-8-isoquinolyl]carbamate (35 mg, 31% yield) as a light yellowsolid. LCMS (ESI) [M+H]⁺=567.3.

Step 4:(±)-cis-N-[8-amino-6-[4-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of (±)-tert-butylN-[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-8-isoquinolyl]carbamate(35 mg, 0.062 mmol) in methanol (2 mL) and 4N HCl-dioxane (2 mL, 8 mmol)was stirred at 30° C. for 2 hours. The reaction mixture wasconcentrated. The residue was dissolved in methanol (1 mL), the pHadjusted by adding 7N NH₃/methanol until pH=9-10 was obtained, andconcentrated. The crude product was purified by flash chromatography(C₁₈, NH₄HCO₃/methanol/water) to afford(±)-cis-N-[8-amino-6-[4-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(11 mg, 50% yield) was as a light brown solid. LCMS (ESI): R_(T)(min)=1.216, [M+H]⁺=353.1, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.25 (s,1H), 8.57 (d, J=5.2 Hz, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.74 (d, J=5.2Hz, 1H), 7.02 (s, 1H), 6.67 (d, J=1.6 Hz, 1H), 4.99-4.95 (m, 0.5H),4.83-4.79 (m, 0.5H), 4.67 (s, 2H), 2.18-2.13 (m, 1H), 1.88-1.77 (m, 1H),1.27-1.18 (m, 1H).

Example 4N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(Compound 4)

Step 1:N-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide

To a solution of 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine (0.25 g,0.78 mmol) in dichloromethane (25 mL) was added pyridine (3 mL) andcyclopropanecarbonyl chloride (0.3 g, 2.84 mmol). The mixture wasstirred at 25° C. for 3 hours. The solution was concentrated. Theresidue was purified by flash column chromatography (30% ethyl acetatein petroleum ether) to giveN-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide (35mg) as a yellow solid. LCMS (ESI) [M+H]⁺=390.9.

Step 2:N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

To a solution ofN-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide (35mg, 0.09 mmol) and 4-methylpyridine-3-boronic acid (13 mg, 0.1 mmol) inwater (2 mL) and THF (5 mL) was added Na₂CO₃ (27 mg, 0.25 mmol) andPd(dppf) Cl₂ (7 mg, 0.01 mmol). The solution was stirred at 65° C. for 3hours. After cooling, the organic layer was concentrated. The crude wasthen purified by flash column chromatography (50% ethyl acetate inpetroleum ether) to giveN-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(20 mg, 63% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=356.1.

Step 3:N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture ofN-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(20 mg, 0.06 mmol), benzophenone imine (15 mg, 0.08 mmol), Pd(OAc)₂ (3mg, 0.01 mmol), Xantphos (5 mg, 0.01 mmol), Cs₂CO₃ (51 mg, 0.16 mmol),DMF (3 mL) and toluene (1 mL) was heated in a microwave reactor at 145°C. for 1 hour. Water (10 mL) was added. The mixture was extracted withethyl acetate (10 mL×3). The organic layer was washed with water (30mL×3), dried over Na₂SO₄, filtered and concentrated. The residue wasre-dissolved in a solution of HCl in 1,4-dioxane (0.73 mL, 4 M, 2.93mmol) and the mixture was stirred at room temperature for 12 hours. Thesolution was concentrated. The residue was washed with a mixture of 10mL petroleum ether and 5 mL of ethyl acetate. The crude was purified byreverse phase prep-HPLC to giveN-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(3 mg, 16% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.819,[M+H]⁺=337.0, method=C; ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 8.54 (d,J=4.8 Hz, 1H), 8.48 (s, 2H), 8.26 (s, 1H), 7.26 (d, J=7.2 Hz, 1H), 7.06(d, J=6.4 Hz, 1H), 4.45 (bs, 2H), 2.26 (s, 3H), 1.63-1.60 (m, 1H),1.16-1.14 (m, 2H), 0.94-0.92 (m, 2H).

Example 5N-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(Compound 5)

Step 1:N-(7-bromo-8-chloro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide

To a solution of 7-bromo-8-chloro-6-iodoisoquinolin-3-amine (3 g, 7.82mmol) in dichloromethane (25 mL) was added pyridine (3 mL) andcyclopropanecarbonyl chloride (3 g, 28.7 mmol). The solution was stirredat 25° C. for 3 hours. The solution was concentrated. The residue waspurified by flash column chromatography (5% methanol in dichloromethane)to giveN-(7-bromo-8-chloro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide (1.2g, 34% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=450.9.

Step 2:N-(7-bromo-8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

To a mixture ofN-(7-bromo-8-chloro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide (300mg, 0.66 mmol) and 4-methylpyridine-3-boronic acid (100 mg, 0.73 mmol)in water (2 mL) and THF (5 mL) was added Na₂CO₃ (200 mg, 1.89 mmol) andPd(dppf)Cl₂ (50 mg, 0.06 mmol). The mixture was stirred at 65° C. for 3hours. After cooling, the organic layer was concentrated. The crudematerial was then purified by flash column chromatography (50% ethylacetate in petroleum ether) to giveN-(7-bromo-8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3yl)cyclopropanecarboxamide(110 mg, 40% yield) as a brown solid. LCMS (ESI) [M+H]⁺=416.0. ¹H NMR(400 MHz, DMSO-d₆): δ 11.21 (s, 1H), 9.43 (s, 1H), 8.55-8.53 (m, 2H),8.37 (s, 1H), 7.94 (s, 1H), 7.42 (d, J=5.2 Hz, 1H), 2.10-2.07 (m, 4H),0.86-0.85 (m, 4H).

Step 3:N-(8-chloro-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture ofN-(7-bromo-8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3yl)cyclopropanecarboxamide(300 mg, 0.72 mmol) and CuCN (300 mg, 3.33 mmol) in1-methyl-2-pyrrolidinone (3 mL) was heated in a microwave reactor at200° C. for 1 hour. The mixture was diluted with ethyl acetate (10 mL)to give a brown precipitate. The mixture was filtered and concentrated.The residue was diluted with ammonium hydroxide (5 mL) and stirred atroom temperature for 1 hour. The mixture was extracted withdichloromethane (30 mL×2) and washed with water (20 mL×2). The organiclayer was concentrated and purified by prep-HPLC to giveN-(8-chloro-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(120 mg, 46% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=363.1. ¹H NMR(400 MHz, CDCl₃): δ 9.48 (s, 1H), 8.62-8. 61 (m, 2H), 8.47 (s, 1H), 8.40(s, 1H), 7.64 (s, 1H), 7.31 (d, J=4.8 Hz, 1H), 2.27 (s, 3H), 1.68-1.62(m, 1H), 1.19-1.15 (m, 2H), 1.01-0.98 (m, 2H).

Step 4:N-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture ofN-(8-chloro-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(20 mg, 0.06 mmol), benzophenoneimine (15 mg, 0.08 mmol), Pd(OAc)₂ (3mg, 0.01 mmol), Xantphos (5 mg, 0.01 mmol), Cs₂CO₃ (50 mg, 0.15 mmol),DMF (3 mL) and toluene (1 mL) were added to a reaction tube in a glovebox. The reaction was then sealed and heated in a microwave reactor at145° C. for 1 hour. Water (10 mL) was added. The mixture was extractedwith ethyl acetate (10 mL×3). The organic layer was washed with water(30 mL×3), dried over Na₂SO₄, filtered and concentrated. The residue wasre-dissolved in a solution of HCl in 1,4-dioxane (0.72 mL, 4 M, 2.87mmol). The mixture was stirred at room temperature for 12 hours. Thesolution was concentrated, washed with a mixture of 10 mL petroleumether and 5 mL of ethyl acetate. The residue was purified by prep-HPLCto giveN-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide(4 mg, 21% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.688,[M+H]⁺=344.1, method=F; ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 8.55 (d,J=5.2 Hz, 1H), 8.47 (s, 1H), 8.46 (s, 1H), 8.25 (s, 1H), 7.27 (d, J=5.2Hz, 1H), 6.99 (s, 1H), 5.43 (bs, 2H), 2.28 (s, 3H), 1.60-1.57 (m, 1H),1.17-1.15 (m, 2H), 0.97-0.96 (m, 2H).

Example 6N-(8-amino-7-cyano-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide (Compound 6)

Step 1:N-(7-bromo-8-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide

To a solution ofN-(7-bromo-8-chloro-6-iodoisoquinolin-3-yl)cyclopropanecarboxamide (250mg, 0.55 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(126 mg, 0.61 mmol) in water (3 mL) and THF (10 mL) was added Na₂CO₃(166 mg, 1.57 mmol) and Pd(dppf)Cl₂ (41 mg, 0.05 mmol). The reactionsolution was stirred under N₂ at 85° C. for 12 hours before beingconcentrated to dryness. The residue was taken up in ethyl acetate (10mL), washed with water and brine, dried over MgSO₄ and concentrated. Thecrude was purified by flash column chromatography (50% ethyl acetate inpetroleum ether) to giveN-(7-bromo-8-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(150 mg, 67% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=405.0.

Step 2:N-(8-chloro-7-cyano-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture ofN-(7-bromo-8-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(150 mg, 0.37 mmol) and CuCN (154 mg, 1.71 mmol) in1-methyl-2-pyrrolidinone (3 mL) was heated in a microwave reactor at200° C. for 1 hour. The reaction mixture was diluted with ammoniumhydroxide (5 mL) and stirred at room temperature for 1 hour. The mixturewas extracted with dichloromethane (30 mL×2). The combined organiclayers were washed with water (20 mL×2), dried and concentrated. Theresidue was purified by flash column chromatography (50% ethyl acetatein petroleum ether) to giveN-(8-chloro-7-cyano-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(50 mg, 38% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=352.1.

Step 3:N-(8-amino-7-cyano-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture ofN-(8-chloro-7-cyano-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(50 mg, 0.14 mmol), benzophenone (39 mg, 0.21 mmol), Pd(OAc)₂ (8 mg,0.03 mmol), Xantphos (13 mg, 0.02 mmol), Cs₂CO₃ (129 mg, 0.4 mmol), DMF(3 mL) and toluene (1 mL) was added to a sealed tube in glove box. Theresulting mixture was heated at 145° C. in microwave reactor for 1 hour.Water (10 mL) was added. The mixture was extracted with ethyl acetate(10 mL×3). The combined organic layer was washed with water (30 mL×3),dried over Na₂SO₄, filtered and concentrated. The residue was dissolvedin a solution of HCl in 1,4-dioxane (1.85 mL, 4M, 7.41 mmol). Themixture was stirred at room temperature for 13 hours. The reactionsolution was concentrated, washed with a mixture of 10 mL petroleumether and 5 mL of ethyl acetate. The residue was purified by prep-HPLCto giveN-(8-amino-7-cyano-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(5 mg, 11% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.724,[M+H]⁺=333.1, method=H; ¹H NMR (400 MHz, CD3OD) δ 9.27 (s, 1H), 8.28 (s,1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.12 (s, 1H), 4.00 (s, 3H), 1.33-1.32(m, 1H), 1.04-1.03 (m, 2H), 0.95-0.92 (m, 2H).

Example 7(±)-[8-amino-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide(Compound 13)

Step 1: 5-bromo-2-chloro-4-methyl-pyrimidine

Tert-butyl nitrite (16 g, 155 mmol) was added dropwise to a mixture of5-bromo-4-methyl-2-pyrimidinylamine (5 g, 26.59 mmol), andbenzyltriethylammoniumchloride (27 g, 118.54 mmol) in dichloromethane(200 mL). The reaction mixture was stirred at 25° C. for 2 hours. Thereaction mixture was diluted with H₂O (50 mL), neutralized with sat.NaHCO₃ and extracted with dichloromethane (300 mL×3). All of thedichloromethane layers were combined, dried over Na₂SO₄, filtered andevaporated. The residue was purified by silica-gel column chromatography(petroleum ether/ethyl acetate=10:1) to give5-bromo-2-chloro-4-methyl-pyrimidine (2.5 g, 45% yield) as a whitesolid. LCMS (ESI) [M+H]⁺=208.9.

Step 2: 5-bromo-4-methyl-pyrimidine-2-carbonitrile

A mixture of 5-bromo-2-chloro-4-methylpyrimidine (2.5 g, 12.08 mmol),sodium cyanide (600 mg, 12.24 mmol), and DABCO (500 mg, 4.46 mmol) indimethyl sulfoxide (40 mL) and water (40 mL) was stirred overnight. Thereaction mixture was diluted with H₂O (100 mL) and extracted with ethylacetate (80 mL×3). The ethyl acetate layers were combined, washed withbrine (50 mL×2), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified with silica-gel column chromatography (petroleumether/ethyl acetate=10:1) to give5-bromo-4-methyl-pyrimidine-2-carbonitrile (1.75 g, 73% yield) as alight yellow solid. LCMS (ESI) [M+H]⁺=199.9.

Step 3: Methyl 5-bromo-4-methyl-pyrimidine-2-carboxylate

A mixture of 5-bromo-4-methyl-pyrimidine-2-carbonitrile (1.35 g, 6.82mmol) in conc. HCl (20 mL) and methanol (20 mL) was refluxed for 2hours. The reaction mixture was concentrated. The residue was dilutedwith water (20 mL), adjusted to pH 7 by adding sat. NaHCO₃ and extractedwith ethyl acetate (30 mL×3). All of ethyl acetate layers were combined,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby silica-gel column chromatography (petroleum ether/ethyl acetate=1:1)to give methyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (940 mg, 60%yield) as a white solid. LCMS (ESI) [M+H]⁺=233.0.

Step 4: 5-bromo-4-methyl-pyrimidine-2-carboxylic acid

A mixture of methyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (300 mg,1.3 mmol) and LiOH monohydrate (160 mg, 3.81 mmol) in THF (5 mL) andwater (5mL) was stirred at 25° C. for 2 hours. The reaction mixture wasconcentrated to remove THF. The residue aqueous layer was diluted withwater (20 mL) and washed with ethyl acetate (20 mL×2). The aqueous layerwas acidified to pH 4-5 by adding conc. HCl. Sodium chloride was addeduntil saturation and the product was then extracted with ethyl acetate(40 mL×5). The combined extracts were combined, dried over Na₂SO₄,filtered and evaporated. 5-bromo-4-methyl-pyrimidine-2-carboxylic acid(230 mg, 81% yield) as a white solid. LCMS (ESI) [M+H]⁺=219.0.

Step 5: 5-bromo-N,4-dimethyl-pyrimidine-2-carboxamide

Oxalyl chloride (200 mg, 1.57 mmol) was added dropwise to a mixture of5-bromo-4-methyl-pyrimidine-2-carboxylic acid (230 mg, 1.06 mmol) in DMF(0.1 mL) and dichloromethane (5 mL) at 0° C. The reaction mixture wasstirred at 25° C. for 0.5 hours and concentrated. The residue wasre-dissolved in dichloromethane (2 mL) and added dropwise to a solutionof CH₃NH₂ (2M in THF, 2 mL, 4 mmol) and pyridine (0.51 mL, 6.33 mmol) indichloromethane (5 mL) at 0° C. The reaction mixture was stirred at 25°C. for 1 hour and evaporated. The residue was purified with silica-gelcolumn chromatography (dichloromethane/ethyl acetate=1:4) to give5-bromo-N,4-dimethyl-pyrimidine-2-carboxamide (240 mg, 98% yield) as awhite solid. LCMS (ESI) [M+H]⁺=230.0.

Step 6: [4-methyl-2-(methylcarbamoyl)pyrimidin-5-yl]boronic acid

A mixture of bis(pinacolato)diboron (200 mg, 0.79 mmol),5-bromo-N,4-dimethyl-pyrimidine-2-carboxamide (100 mg, 0.43 mmol),PdCl₂dppf (20 mg, 0.03 mmol), potassium acetate (120 mg, 1.22 mmol) in1,4-dioxane (8 mL) was stirred under Ar at 80° C. overnight. Thereaction mixture of [4-methyl-2-(methylcarbamoyl)pyrimidin-5-yl]boronicacid was used directly in next step. LCMS (ESI) [M+H]⁺=196.1.

Step 7:(±)-5-[8-chloro-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(100 mg, 0.29 mmol), [4-methyl-2-(methylcarbamoyl)pyrimidin-5-yl]boronicacid (reaction mixture, about 8 mL, about 0.43 mmol), PdCl₂dppf (20 mg,0.03 mmol), K₂CO₃ (120 mg, 0.87 mmol) and water (2 mL) was stirred underAr at 80° C. for 2 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (100 mL) and washed with brine(30 mL). The organic layer was separated, dried over Na₂SO₄, filteredand concentrated. The residue was purified with silica gel columnchromatography (petroleum ether/ethyl acetate=1:2) to give(±)-5-[8-chloro-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide(20 mg, 17% yield) as a light brown solid. LCMS (ESI) [M+H]⁺=414.0.

Step 8:(±)-5-[8-(benzhydrylideneamino)-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide

A mixture of(±)-5-[8-chloro-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide(20 mg, 0.048 mmol), benzophenone imine (80 mg, 0.44 mmol), Pd₂dba₃ (10mg, 0.01 mmol), Xantphos (10 mg, 0.02 mmol), Cs₂CO₃ (40 mg, 0.12 mmol)in DMF (1 mL) and toluene (1 mL) was stirred under Ar at 130° C. for 1.5hours. The reaction mixture was cooled to room temperature. The residuewas diluted with ethyl acetate (80 mL) and washed with water (20 mL).The organic layer was separated, dried over Na₂SO₄, filtered andevaporated. The residue was purified with silica-gel columnchromatography (petroleum ether/ethyl acetate=1:2 todichloromethane/ethyl acetate=1:3) to give(±)-5-[8-(benzhydrylideneamino)-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide(12 mg, 44% yield) as a yellow solid. LCMS (ESI) [M+I-I]⁺=559.2.

Step 9:(±)-5-[8-amino-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide

A mixture of(±)-5-[8-(benzhydrylideneamino)-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide(12 mg, 0.021 mmol) in water (0.1 ml), 2,2,2-trifluoroacetic acid (0.5ml) and dichloromethane (3 ml) was stirred at 30° C. for 1 hour. Thereaction mixture was evaporated. The residue was dissolved in methanol(1 mL), neutralized with 7N NH₃ in methanol until pH 9-10, and purifiedby flash chromatography (C₁₈, methanol/water to formicacid/methanol/water) to give the formic acid salt of(±)-5-[8-amino-3-[(cis-2-fluorocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-pyrimidine-2-carboxamide(3.4 mg, 37% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.493,[M+H]⁺=395.1, method=E; ¹H NMR (400 MHz, CD₃OD) δ 9.27 (s, 1H), 8.77 (s,1H), 8.52 (brs, 1H), 8.36 (s, 1H), 7.09 (s, 1H), 6.72 (s, 1H), 4.99-4.79(m, 1H), 3.04 (s, 3H), 2.65 (s, 3H), 2.18-2.13 (m, 1H), 1.88-1.78 (m,1H), 1.27-1.19 (m, 1H).

Example 8(±)-cis-N-(8-amino-6-(6-methyl-1H-benzo[d]imidazol-5-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 14)

Step 1: (±)-tert-butyl5-(8-chloro-3-(cis-2-fluorocyclopropanecarboxamido)isoquinolin-6-yl)-6-methyl-1H-benzo[d]imidazole-1-carboxylate

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(80 mg, 0.23 mmol), tert-butyl6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-carboxylate(83 mg, 0.23 mmol), Pd(dppf)Cl₂ (17 mg, 0.02 mmol) and K₂CO₃ (96 mg,0.70 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was stirred at 90° C.for 4 hours. The reaction mixture was concentrated. The residue waspurified by prep-TLC (normal phase silica gel, uv 254 nm,dichloromethane/methanol=30/1) to give (±)-tert-butyl5-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-6-methyl-benzimidazole-1-carboxylate(70 mg, 60% yield) as a yellow oil.

Step 2:(±)-cis-N-(8-amino-6-(6-methyl-1H-benzo[d]imidazol-5-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added (±)-tert-butyl5-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-6-methyl-benzimidazole-1-carboxylate(60 mg, 0.12 mmol), tert-butyl carbamate (142 mg, 1.21 mmol), Pd₂(dba)₃(23 mg, 0.03 mmol), NaOtBu (34 mg, 0.36 mmol), tBuBrettPhos (13 mg, 0.03mmol) and 1-methyl-2-pyrrolidinone (4 mL). The mixture was stirred at110° C. for 2 hours. The reaction mixture was concentrated in vacuum.The residue was purified by reverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(6-methyl-1H-benzimidazol-5-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(5 mg, 11% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.335,[M+H]⁺=376.1, method=C; ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 8.30 (s,1H), 8.16 (s, 1H), 7.59-7.47 (m, 2H), 7.03 (s, 1H), 6.76 (s, 1H),4.99-4.78 (m, 1H), 2.40 (s, 3H), 2.20-2.12 (m, 1H), 1.87-1.76 (m, 1H),1.27-1.17 (m, 1H).

Example 9(±)-cis-N-(8-amino-6-(5-cyclopropylpyridazin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 15)

Step 1: 8-chloro-6-(cyclopropylethynyl)isoquinolin-3-amine

A mixture of ethynylcyclopropane (500 mg, 7.56 mmol), CuI (50 mg, 0.26mmol), 6-bromo-8-chloro-isoquinolin-3-amine (200 mg, 0.78 mmol), Et₃N(785 mg, 7.77 mmol) and Pd(PPh₃)₂Cl₂ (62 mg, 0.08 mmol) in DMF (2 mL)was heated at 110° C. for 16 hours. The reaction solution was dilutedwith ethyl acetate, washed with saturated aqueous NH₄Cl (20 mL×3), driedover Na₂SO₄, filtered and concentrated. The residue was purified byprep-TLC (normal phase silica gel, dichloromethane/methanol=25/1) togive 8-chloro-6-(2-cyclopropylethynyl) isoquinolin-3-amine (170 mg, 81%yield) as a yellow solid.

Step 2: 8-chloro-6-(5-cyclopropylpyridazin-4-yl)isoquinolin-3-amine

A solution of 1,2,4,5-tetrazine (80 mg, 0.97 mmol) and8-chloro-6-(2-cyclopropylethynyl)isoquinolin-3-amine (60 mg, 0.25 mmol)in p-xylene (3 mL) was stirred at 140° C. for 18 hours. The reactionsolution was concentrated. The residue was purified by prep-TLC (normalphase silica gel, dichloromethane/methanol=30/1) to give8-chloro-6-(5-cyclopropylpyridazin-4-yl)isoquinolin-3-amine (40 mg, 55%yield) as a yellow oil.

Step 3:(±)-cis-N-(8-chloro-6-(5-cyclopropylpyridazin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a solution of(±)-8-chloro-6-(5-cyclopropylpyridazin-4-yl)isoquinolin-3-amine (100 mg,0.34 mmol) in dichloromethane (10 mL) and pyridine (0.08 mL, 1.01 mmol)was added a solution of cis-2-fluorocyclopropanecarbonyl chloride (0.13g, 1.08 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirredat 20° C. for 1 hour before concentrated under vacuum. The residue waspurified by prep-TLC (normal phase, silica gel, petroleum ether/ethylacetate=4:1) to give(±)-cis-N-[8-chloro-6-(5-cyclopropylpyridazin-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 77% yield) as a yellow solid.

Step 4:(±)-cis-N-(8-amino-6-(5-cyclopropylpyridazin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added(±)-cis-N-[8-chloro-6-(5-cyclopropylpyridazin-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(80 mg, 0.21 mmol), tert-butyl carbamate (244 mg, 2.09 mmol), Pd₂(dba)₃(19 mg, 0.02 mmol), NaOtBu (59 mg, 0.62 mmol), tBuBrettPhos (10 mg, 0.02mmol) and 1-methyl-2-pyrrolidinone (3 mL). The mixture was stirred at110° C. for 2 hours. The reaction mixture was concentrated in vacuum.The residue was purified by reverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(5-cyclopropylpyridazin-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(8 mg, 10% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.566,[M+H]⁺=364.1, method=C; ¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 9.00 (s,1H), 8.78 (s, 1H), 8.37 (s, 1H), 7.18 (s, 1H), 6.80 (s, 1H), 4.99-4.78(m, 1H), 2.21-2.08 (m, 2H), 1.88-1.76 (m, 1H), 1.27-1.17 (m, 3H),1.12-1.06 (m, 2H).

Example 10 (±)-cis-N-(8-amino-6-(7-methyl-3H-imidazo[4,5-b]pyridin-6-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (Compound 16)

Step 1: (±)-cis-N-(8-chloro-6-(7-methyl-3H-imidazo[4,5-b]pyridin-6-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(300 mg, 0.87 mmol),7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine(280 mg, 1.08 mmol), Pd(dppf)Cl₂ (60 mg, 0.08 mmol), K₂CO₃ (350 mg, 2.54mmol) in 1,4-dioxane (6 mL) and water (1 mL) was stirred under an Aratmosphere at 110° C. for 3 hours. The reaction was concentrated todryness. The crude product was then purified by column chromatography(ethyl acetate/petroleum ether=1:1) to afford(±)-cis-N-[8-chloro-6-(7-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(280 mg, 64% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=396.1.

Step 2:(±)-cis-N-(8-chloro-6-(7-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridin-6-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A solution of(±)-cis-N-[8-chloro-6-(7-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(280 mg, 0.71 mmol), 3,4-dihydro-2H-pyran (1.0 mL, 10.96 mmol), andtrifluoroacetic acid (0.1 mL, 1.34 mmol) in dichloromethane (15 mL) washeated overnight at reflux. The reaction was then diluted with 5 mL of asaturated NaHCO₃ solution was added. The organic layer was thenseparated, dried (Na₂SO₄) and concentrated. The crude was then purifiedby column chromatography on silica gel (ethyl acetate/petroleumether=1:10) to afford(±)-cis-N-[8-chloro-6-(7-methyl-3-tetrahydropyran-2-yl-imidazo[4,5-b]pyridin-6-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(160 mg, 46% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=480.2.

Step 3: (±)-tert-butyl3-(cis-2-fluorocyclopropanecarboxamido)-6-(7-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridin-6-yl)isoquinolin-8-ylcarbamate

A mixture of(±)-cis-N-[8-chloro-6-(7-methyl-3-tetrahydropyran-2-yl-imidazo[4,5-b]pyridin-6-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(50 mg, 0.10 mmol), tert-butyl carbamate (120 mg, 1.02 mmol), Xantphos(25 mg, 0.04 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), sodium tert-butoxide(50 mg, 0.52 mmol) in dry DMF (2.0 mL) and dry toluene (2.0 mL) wasstirred overnight at 115° C. The reaction was concentrated. The residuewas taken up in ethyl acetate (15 ml). The mixture was washed with 20 mLof saturated brine solution. The organic layer was then separated, dried(Na₂SO₄) and concentrated. The crude was purified by columnchromatography on silica gel (ethyl acetate/petroleum ether, 1/5 to 1/1)to afford (±)-tert-butylN-[3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-(7-methyl-3-tetrahydropyran-2-yl-imidazo[4,5-b]pyridin-6-yl)-8-isoquinolyl]carbamate(60 mg, 60% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=477.1.

Step 4: (±)-cis-N-(8-amino-6-(7-methyl-3H-imidazo[4,5-b]pyridin-6-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A solution of (±)-tert-butylN-[3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-(7-methyl-3-tetrahydropyran-2-yl-imidazo[4,5-b]pyridin-6-yl)-8-isoquinolyl]carbamate(60 mg, 0.06 mmol) in methanol (1 mL) and HCl (4M in dioxane, 1.0 mL, 4mmol) was stirred at room temperature for 1 hour. The reaction waspurified by reverse phase prep-HPLC to afford(±)-cis-N-[8-amino-6-(7-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(9 mg, 38% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=377.2,Rt(min)=1.42, Method=E; ¹HNMR (400 MHz,CD₃OD) δ 9.25 (s, 1H), 8.43 (s,1H), 8.33 (s, 2H), 7.06 (s, 1H), 6.76 (d, J=1.6 Hz, 1H), 4.99-4.79 (m,1H), 2.65 (s, 3H), 2.18-2.13 (m, 1H), 1.88-1.77 (m, 1H), 1.27-1.18 (m,1H).

Example 11 (±)-cis-N-(8-amino-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluoro cyclopropanecarboxamide (Compound 17)

Step 1:5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-bromo-3-isopropyl-1H-pyrazole (380 mg, 2.01 mmol),Pd(dppf)Cl₂ (140 mg, 0.19 mmol), potassium acetate (800 mg, 8.16 mmol),bis(pinacolato)diboron (4750 mg, 18.71 mmol) in 1,4-dioxane (20 mL) wasstirred under an inert atmosphere at 110° C. for 5 hours. The reactionwas concentrated to dryness. The crude was then purified by columnchromatography on silica gel (ethyl acetate /petroleum ether=1:1) toafford5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(400 mg , 28% yield) as a red liquid. LCMS (ESI): [M+H]⁺=237.2.

Step 2: (±)-cis-N-(8-chloro-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube containing the reaction mixture of5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(400 mg, 0.56 mmol), Pd(dppf)Cl₂ (35 mg, 0.05 mmol), K₂CO₃ (200mg, 1.45mmol), and(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(150 mg, 0.44 mmol) in 1,4-dioxane (6 mL) and water (1 mL). The reactionmixture was heated at 130° C. in a microwave for 1 hour. The reactionwas concentrated to dryness. The crude was then purified by columnchromatography on silica gel (ethyl acetate) to afford crude(±)-cis-N-[8-chloro-6-(5-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(200 mg, 50% yield) as a yellow liquid. LCMS (ESI): [M+H]⁺=373.1.

Step 3:(±)-cis-N-(8-chloro-6-(5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A solution of(±)-cis-N-[8-chloro-6-(5-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(200 mg, 0.22 mmol), 3,4-dihydro-2H-pyran (1.0 mL, 10.96 mmol), andtrifluoroacetic acid (0.1 mL, 1.34 mmol) in dichloromethane (15 mL) wasrefluxed overnight. The reaction was then concentrated to dryness. Thecrude was then purified by column chromatography on silica gel(petroleum ether/ethyl acetate=10/1) to afford(±)-cis-N-[8-chloro-6-(5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(80 mg, 70% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=457.2.

Step 4: (±)-cis-N-(8-amino-6-(5sopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-(5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(70 mg, 0.15 mmol), tert-butyl carbamate (100 mg, 0.85 mmol), Xantphos(35 mg, 0.06 mmol), Pd₂(dba)₃ (25 mg, 0.03 mmol), and Cs₂CO₃ (200 mg,0.62 mmol) in dry DMF (1 mL) and dry toluene (1 mL) was stirred at 130°C. under an inert atmosphere for 4 hours. The reaction was thenconcentrated and purified by reverse phase chromatography (methanol40-60/0.05% ammonia in water) to afford(±)-cis-N-[8-amino-6-(5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide (25 mg, 37% yield) as a white solid. LCMS (ESI):[M+H]⁺=438.2.

Step 5: (±)-cis-N-(8-amino-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A solution of(±)-cis-N-[8-amino-6-(5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(25 mg, 0.06 mmol) in HCl in 1,4-dioxane (4M, 1.0 mL, 4.0 mmol) wasstirred at room temperature for 30 minutes. The resulting mixture waspurified by reverse phase chromatography (methanol 60%/0.05% ammonia inwater) to afford(±)-cis-N-[8-amino-6-(5-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(9 mg, 43% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.57,[M+H]⁺=354.1, method=E; ¹H NMR (400 MHz, CD₃OD) δ 9.17(s, 1H), 8.26 (s,1H), 7.69 (s, 1H), 7.07 (s, 1H), 6.83 (d, J=0.9 Hz, 1H), 4.99-4.92 (m,0.5H), 4.83-4.79 (m, 0.5H), 3.45-3.44 (m, 1H) , 2.17-2.13 (m, 1H),1.87-1.79 (m, 1H), 1.37-1.35 (d, J=6.8 Hz, 6H), 1.27-1.18 (m, 1H).

Example 12(±)-cis-N-(8-amino-6-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 18)

Step 1:4-iodo-5-methylpyridin-2-ol

A mixture of 4-iodo-2-methoxy-5-methyl-pyridine (700 mg, 2.81 mmol),iodide trimethylsilane (752 mg, 3.76 mmol) in acetonitrile (10 mL) washeated to reflux for 2 hours. The reaction was then concentrated todryness. The crude product was then purified by column chromatography onsilica gel (ethyl acetate) to afford 4-iodo-5-methyl-pyridin-2-ol (500mg, 71% yield) as a white solid. LCMS (ESI): [M+H]⁺=235.9.

Step 2: 1-ethyl-4-iodo-5-methylpyridin-2(1H)-one

A mixture of 4-iodo-5-methyl-pyridin-2-ol (480 mg, 2.04 mmol) and sodiumhydride (60% in mineral oil, 200 mg, 5 mmol) in DMF (5 mL) was stirredat room temperature for 20 minutes. Iodoethane (0.5 mL, 6.25 mmol) wasthen added. The mixture was stirred at room temperature for 1 hour. Themixture was purified by reverse phase chromatography (methanol 60%/0.1%ammonia in water) to afford 1-ethyl-4-iodo-5-methyl-pyridin-2-one (250mg, 47% yield) as a white solid. LCMS (ESI): [M+H]⁺=264.0.

Step3:(±)-cis-N-(8-chloro-6-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of 1-ethyl-4-iodo-5-methyl-pyridin-2-one (120 mg, 0.46 mmol),Pd(dppf)Cl₂ (30 mg, 0.04 mmol), potassium phosphate (400 mg, 1.89 mmol),and(±)-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]boronicacid (140 mg, 0.45 mmol) in 1,4-dioxane (6 mL) and water (1 mL) wasstirred at 100° C. for 1 hour. The reaction was concentrated to dryness.The crude was then purified by column chromatography on silica gel(ethyl acetate) to afford(±)-cis-N-[8-chloro-6-(1-ethyl-5-methyl-2-oxo-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(70 mg, 37% yield) as a white solid. LCMS (ESI): [M+H]⁺=400.1.

Step 4:(±)-cis-N-(8-amino-6-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-(1-ethyl-5-methyl-2-oxo-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(50 mg, 0.13 mmol), tert-butyl carbamate (155 mg, 1.32 mmol), Xantphos(30 mg, 0.05 mmol), Pd₂(dba)₃ (25 mg, 0.03 mmol), and Cs₂CO₃ (200 mg,0.62 mmol) in dry DMF(2 mL) and dry toluene (2 mL) was stirred overnightunder inert atmosphere at 112° C. The reaction was then concentrated andpurified by reverse phase chromatography (acetonitrile 0-40/0.1% HCl inwater) to afford(±)-cis-N-[8-amino-6-(1-ethyl-5-methyl-2-oxo-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(8.1 mg, 17% yield) as a formate salt (yellow solid). LCMS(ESI): R_(T)(min)=1.44 , [M+H]⁺=381.1, method=A; ¹H NMR (400 MHz,CD₃OD) δ 9.24 (s,1H), 8.32 (s, 1H), 7.58 (s, 1H), 6.96 (s, 1H), 6.63 (d, J=0.8 Hz, 1H),6.49 (s, 1H), 4.97-4.80 (m, 1H), 4.108 (q, J=7.2 Hz, 2H) , 2.17-2.14(m,1H), 2.05 (s, 3H), 1.86-1.79 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.25-1.20(m, 1H).

Example 13 (±)-cis-N-(8-amino-6-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (Compound 19)

Step 1: (±)-cis-N-(8-chloro-6-(2-methoxy-5-methylpyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of 4-iodo-2-methoxy-5-methyl-pyridine (255 mg, 1.02 mmol),Pd(dppf)Cl₂ (40 mg, 0.05 mmol), K₃PO₄ (350 mg, 1.65 mmol),[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]boronic acid (220 mg, 0.71 mmol) in 1,4-dioxane (6mL) and water (1 mL) was stirred at 100° C. for 1 hour. The reactionmixture was concentrated to dryness. The crude was then purified bycolumn chromatography on silica gel (petroleum ether/ethyl acetate=5/1)to afford(±)-cis-N-[8-chloro-6-(2-methoxy-5-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 35% yield) as a white solid. LCMS (ESI): [M+H]⁺=386.1.

Step 2: (±)-cis-N-(8-amino-6-(2-methoxy-5-methylpyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-(2-methoxy-5-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 0.26 mmol), tert-butyl carbamate (200 mg, 1.71 mmol), Xantphos(60 mg, 0.10 mmol), Pd₂(dba)₃ (50 mg, 0.05 mmol), Cs₂CO₃ (420 mg, 1.29mmol) in dry DMF (2 mL) and dry toluene (2 mL) was stirred at 115° C.under Ar for 4 hours. The reaction was concentrated to dryness. Thecrude was then purified by column chromatography on silica gel elutedethyl acetate/petroleum ether (1:1) to afford crude(±)-cis-N-[8-amino-6-(2-methoxy-5-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide (25 mg) as a yellow solid. LCMS (ESI): [M+H]⁺=367.2.

Step 3: (±)-cis-N-(8-amino-6-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-[8-amino-6-(2-methoxy-5-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(35 mg, 0.05 mmol) and iodotrimethylsilane (30 mg, 0.15 mmol) inacetonitrile (10 mL) was heated to reflux for 2 hours. Then 0.5 mL ofsaturated Na₂S₂O₃ solution was added and the reaction was concentrated.The resulting residue was purified by reverse phase chromatography(methanol 40-50/0.05% ammonia in water) to afford(±)-cis-N-[8-amino-6-(5-methyl-2-oxo-1H-pyridin-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(9 mg, 53% yield) as a yellow solid. LCMS(ESI):R_(T) (min)=1.45,[M+H]⁺=353.1, method=B; ¹H NMR (400 MHz, DMSO-d₆) δ 11.53-11.49 (m, 1H),10.81 (s, 1H), 9.32 (s, 1H), 8.27 (s, 1H), 7.28 (s, 1H), 6.85 (s, 1H),6.49 (s, 1H), 6.34 (s, 2H), 6.19 (s, 1H), 5.0-4.83 (m, 1H), 2.28-2.22(m, 1H), 1.91 (s, 3H), 1.71-1.63 (m, 1H), 1.21-1.14 (m, 1H).

Example 141-(8-amino-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-sopropylurea(Compound 20)

Step 1: 8-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine

To a sealed tube was added 6-bromo-8-chloro-isoquinolin-3-amine (300 mg,1.17 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole(364 mg, 1.75 mmol), Pd(dppf)Cl₂(105 mg, 0.14 mmol), Na₂CO₃ (375 mg,3.54 mmol), 1,4-dioxane (15 mL) and water (1.5 mL). The mixture wasbubbled through with N₂ for 2 min, and stirred at 100° C. for 2.5 hours.The mixture was concentrated in vacuo and then purified by columnchromatography (silica-gel column, petroleum ether/ethyl acetate from1:1 to 0:100, uv 254 nm) to get8-chloro-6-(1-methylpyrazol-4-yl)isoquinolin-3-amine (290 mg, 94% yield)as a yellow solid. LCMS (ESI) [M+H]⁺=259.1.

Step 2:1-(8-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-isopropylurea

To a pressure tube was added8-chloro-6-(1-methylpyrazol-4-yl)isoquinolin-3-amine (280 mg, 1.08mmol), isopropyl isocyanate (1 mL, 10.18 mmol), and DBU (494 mg, 3.25mmol). The mixture was stirred at 100° C. for 4 hours. The mixture wasconcentrated and purified by column chromatography (20 g silica-gelcolumn, eluted with petroleum ether/ethyl acetate from 1:1 to 0:100) togive1-[8-chloro-6-(1-methylpyrazol-4-yl)-3-isoquinolyl]-3-isopropyl-urea(200 mg, 52% yield) as yellow solid. LCMS (ESI) [M+H]⁺=344.1.

Step 3:1-(8-amino-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-isopropylurea

To a sealed tube was added1-[8-chloro-6-(1-methylpyrazol-4-yl)-3-isoquinolyl]-3-isopropyl-urea(180 mg, 0.52 mmol), tert-butyl carbamate (500 mg, 4.27mmol), Pd₂(dba)₃(100 mg, 0.11 mmol), NaOtBu (150 mg, 1.56 mmol), tBuBrettPhos (60 mg,0.12 mmol) and 1-methyl-2-pyrrolidinone(15 mL). The mixture was stirredat 110° C. for 2 hours. The reaction mixture was concentrated undervacuum. The residue was purified by column chromatography (10 mmol/LNH₄HCO₃ aq./acetonitrile from 100:0 to 1:5) to give1-[8-amino-6-(1-methylpyrazol-4-yl)-3-isoquinolyl]-3-isopropyl-urea (31mg, 18% yield) as a pale-brown solid. LCMS (ESI): R_(T) (min)=1.167,[M+H]⁺=325.2, method=B; ¹H NMR (400 MHz, CD₃OD) δ: 8.94 (s, 1H), 7.92(s, 1H), 7.78 (s, 1H), 7.35 (s, 1H), 7.06 (s, 1H), 6.76 (d, J=1.6 Hz,1H), 3.92-3.85 (m, 1H), 3.85 (s, 3H), 1.15 (d, J=6.4 Hz, 6H).

Example 15(±)-trans-N-[8-amino-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 21)

Step 1:4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.54 mmol),bis(pinacolato)diboron (1289 mg, 5.08 mmol), Pd(dppf)Cl₂ (186 mg, 0.25mmol) and potassium acetate (497 mg, 5.08 mmol) in 1,4-dioxane (18 mL)was stirred under Ar at 90° C. for 3 hours. The mixture was concentratedand purified by column chromatography (ethyl acetate/hexane=1:1) toafford4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(480 mg, 78% yield) as a white solid. LCMS (ESI) [M+H]⁺=245.1.

Step 2:(±)-trans-N-[8-chloro-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(180 mg, 0.51 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrrolo[2,3-b]pyridine(150 mg, 0.62 mmol), Pd(PPh₃)₄ (59 mg, 0.05 mmol) and Na₂CO₃ (109 mg,1.03 mmol) in 1,4-dioxane (2 mL) and water (0.1 mL) was stirred under Arat 90° C. for 3 hours. The mixture was concentrated and purified bycolumn chromatography (ethyl acetate/hexane=2:1) to afford(±)-trans-N-[8-chloro-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(210 mg, 65% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=388.1.

Step 3:(±)-trans-N-[8-chloro-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a solution of(±)-trans-N-[8-chloro-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.16 mmol) in DMF(3 mL) was added NaH (13 mg, 0.32 mmol) at 0°C. The mixture was stirred at 0° C. for 0.5 hours. Methyl4-methylbenzenesulfonate (30 mg, 0.16 mmol) was then added. The reactionwas stirred at 0° C. for 2 hours. The crude mixture was purified bypreparative reverse phase HPLC (C-18, acetonitrile/water+0.05% NH₄HCO₃)to give(±)-trans-N-[8-chloro-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(110 mg, 53% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=402.1.

Step 4:(±)-trans-N-[8-(benzhydrylideneamino)-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(110 mg, 0.09 mmol), Pd₂(dba)₃ (16 mg, 0.02 mmol), Xantphos (20 mg, 0.04mmol), Cs₂CO₃ (57 mg, 0.18 mmol) and benzophenone imine (48 mg, 0.26mmol) in DMF (3 ml) and toluene (3 mL) was stirred under Ar at 130° C.for 2.5 hours. Ethyl acetate (80 mL) was added. The mixture was washedwith brine (3×50 mL), dried with Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by column chromatography(ethyl acetate/hexane, 1:1) to afford(±)-trans-N-[8-(benzhydrylideneamino)-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(31 mg, 59% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=547.3.

Step 5:(±)-trans-N-[8-amino-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(31 mg, 0.06 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (10 mL) and water (2 mL) was stirred at 25° C. for 2hours. The reaction mixture was neutralized with NH₄OH to pH=7-8. Themixture was concentrated and purified by reverse phase prep-HPLC (C18,acetonitrile/water+0.05% NH₄HCO₃) to give(±)-trans-N-[8-amino-6-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(16 mg, 69% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.479,[M+H]⁺=383.1, method=A; ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 9.37(s, 1H), 8.36 (d, J=4.8 Hz, 1H), 8.32 (s, 1H), 7.62 (d, J=3.2 Hz, 1H),7.28 (s, 1H), 7.27 (d, J=4.8 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H), 6.69 (d,J=3.2 Hz, 1H), 6.44 (s, 2H), 3.88 (s, 3H), 2.80-2.75 (m, 1H), 2.18-2.13(m, 1H), 1.63-1.58 (m, 1H), 1.47-1.42 (m, 1H).

Example 16(±)-trans-N-[8-amino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 22)

Step 1:(±)-trans-N-[8-chloro-6-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a solution of(±)-trans-N-[8-chloro-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(170 mg, 0.27 mmol) in DMF (10 mL) was added NaH (22 mg, 0.54 mmol) at0° C. The mixture was stirred at 0° C. for 0.5 hours. Tosyl chloride(104 mg, 0.54 mmol) was added and the reaction mixture was stirred at 0°C. for 2 hours. The mixture was purified by reverse phase prep-HPLC(C-18; acetonitrile/water+0.05% NH₄HCO₃) to give(±)-trans-N-[8-chloro-6-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(169 mg, 79% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=542.1.

Step 2:(±)-trans-N-[8-(benzhydrylideneamino)-6-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(170 mg, 0.22 mmol), Pd₂(dba)₃ (40 mg, 0.04 mmol), Xantphos (50 mg, 0.09mmol), Cs₂CO₃ (140 mg, 0.43 mmol) and benzophenone imine (118 mg, 0.65mmol) in DMF (6 mL) and toluene (6 mL) was stirred under Ar at 130° C.for 2.5 hours. Ethyl acetate (180 mL) was added. The mixture was washedwith brine (3×50 mL), dried with Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by column chromatography(ethyl acetate/hexane=1: 1) to afford(±)-trans-N-[8-(benzhydrylideneamino)-6-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 67% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=687.2.

Step 3:(±)-trans-N-[8-(benzhydrylideneamino)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.15 mmol) and TBAF (152 mg, 0.58 mmol) in THF (15 mL) wasstirred at 50° C. for 24 hours. The mixture was concentrated andpurified by reverse phase prep-HPLC (C18; acetonitrile/water+0.05%NH₄HCO₃) to give(±)-trans-N-[8-(benzhydrylideneamino)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(68 mg, 88% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=533.2.

Step 4:(±)-trans-N-[8-amino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(68 mg, 0.13 mmol) in acetonitrile (10 mL), 2,2,2-trifluoroacetic acid(1 mL) and water (10 mL) was stirred at 25° C. for 20 minutes. Thereaction mixture was neutralized with NH₄OH to pH=7-8. The mixture wasconcentrated and purified by reverse phase prep-HPLC (C₁₈,acetonitrile/water+0.05% NH₄HCO₃) to give(±)-trans-N-[8-amino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(35 mg, 74% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.392,[M+H]⁺=369.1, method=A. ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H),11.11(s, 1H), 9.36 (s, 1H), 8.31 (s, 1H), 8.30 (d, J=5.2 Hz, 1H), 7.56(t, J=2.8 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J=4.8 Hz, 1H), 7.04 (d, J=1.2Hz, 1H), 6.67 (q, J=1.7 Hz, 1H), 6.42 (s, 2H), 2.79-2.75 (m, 1H),2.17-2.12 (m, 1H), 1.62-1.57 (m, 1H), 1.47-1.42 (m, 1H).

Example 17(±)-trans-N-[8-amino-6-(3-ethyl-1-methyl-6-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 23)

Step 1: 6-bromo-1-methyl-pyridin-2-one

To a mixture of 6-bromo-1H-pyridin-2-one (5.0 g, 28.74 mmol) and K₂CO₃(7.93 g, 57.47 mmol) in acetonitrile (100 mL) was added iodomethane(8.16 g, 57.47 mmol). The mixture was stirred overnight. The mixture wasthen filtered. The filtrate was concentrated and purified by flashcolumn chromatography (50% ethyl acetate in petroleum ether) to afford6-bromo-1-methyl-pyridin-2-one (4.5 g, 83% yield) as a white solid. LCMS(ESI): [M+H]⁺=189.9.

Step 2: 6-bromo-5-iodo-1-methyl-pyridin-2-one

A mixture of 6-bromo-1-methyl-pyridin-2-one (3.7 g, 19.68 mmol) and NIS(4.43 g, 25.58 mmol) in DMF (15 mL) was stirred for 2 days at roomtemperature. The mixture was purified by prep-TLC (petroleum ether/ethylacetate=2/1) to give 6-bromo-5-iodo-1-methyl-pyridin-2-one (1.1 g, 18%yield) as a yellow solid. LCMS (ESI): [M+H]⁺=313.9; ¹H NMR (400 MHz,CD₃OD) δ 7.68(d, J=9.6 Hz, 1H), 6.27(d, J=9.6 Hz, 1H), 3.77(s, 3H).

Step 3: 6-bromo-1-methyl-5-vinyl-pyridin-2-one

A mixture of 6-bromo-5-iodo-1-methyl-pyridin-2-one (1000 mg, 3.19 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1471 mg, 9.56 mmol),Pd(PPh₃)₄ (367 mg, 0.32 mmol), and K₂CO₃ (879 mg, 6.37 mmol) in1,4-dioxane (50 mL) and water (2 mL) was stirred under N₂ at 60° C. for18 hours. The mixture was concentrated and purified by prep-TLC(petroleum ether/ethyl acetate=4/1) to give6-bromo-1-methyl-5-vinyl-pyridin-2-one (600 mg, 68% yield) as whitesolid. LCMS (ESI): [M+H]⁺=216.0.

Step 4: 6-bromo-5-ethyl-1-methyl-pyridin-2-one

To a 25 mL flask was added 6-bromo-1-methyl-5-vinyl-pyridin-2-one (500mg, 2.34 mmol), Pt/C (80 mg, 2.34 mmol) and ethyl acetate (15 mL), themixture was stirred at room temperature under a H₂ atmosphere for 10minutes. The mixture was filtered and the filtrate was concentrated. Thecrude product was purified by prep-TLC eluting with petroleumether/ethyl acetate (2:1) to afford6-bromo-5-ethyl-1-methyl-pyridin-2-one (470 mg, 89% yield) as a whitesolid. LCMS (ESI): [M+H]⁺=218.0.

Step 5:6-(3-amino-8-chloro-6-isoquinolyl)-5-ethyl-1-methyl-pyridin-2-one

To a sealed tube was added (3-amino-8-chloro-6-isoquinolyl)boronic acid(494 mg, 2.22 mmol), 6-bromo-5-ethyl-1-methyl-pyridin-2-one (400 mg,1.85 mmol), Pd(dppf) Cl₂ (151 mg, 0.21 mmol), K₃PO₄ (355 mg, 1.68 mmol),sodium acetate (414 mg, 5.05 mmol), acetonitrile (20 mL) and water (2mL). The mixture was bubbled through with N₂ for 2 minutes, and stirredat 90° C. for 3 hours. The mixture was concentrated and purified byprep-TLC (petroleum ether/ethyl acetate, 1/4) to give6-(3-amino-8-chloro-6-isoquinolyl)-5-ethyl-1-methyl-pyridin-2-one (210mg, 26% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=314.1.

Step 6:(±)-trans-N-(8-chloro-6-(3-ethyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of6-(3-amino-8-chloro-6-isoquinolyl)-5-ethyl-1-methyl-pyridin-2-one (180mg, 0.57 mmol) and pyridine (0.14 mL, 1.72 mmol) in dichloromethane (15mL) was added (±)-trans-2-cyanocyclopropanecarbonyl chloride (111 mg,0.86 mmol). The mixture was stirred at 25° C. for 30 minutes. Themixture was concentrated and purified by prep-TLC to give(±)-trans-N-[8-chloro-6-(3-ethyl-1-methyl-6-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(120 mg, 45% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=407.1.

Step 7:(±)-trans-N-[8-amino-6-(3-ethyl-1-methyl-6-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (345 mg, 2.95 mmol),Pd₂(dba)₃ (54 mg, 0.06 mmol), Cs₂CO₃ (288 mg, 0.88 mmol), Xantphos (57mg, 0.12 mmol),(±)-trans-N-[8-chloro-6-(3-ethyl-1-methyl-6-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(120 mg, 0.29 mmol), DMF (3 mL) and toluene (3 mL) in a glove box. Themixture was stirred at 110° C. for 18 hours. The mixture was taken up inethyl acetate (50 ml) and washed with brine. The organic layer was thenseparated, dried (Na₂SO₄) and concentrated to dryness. The crude wasthen purified by reverse phase prep-HPLC to give(±)-trans-N-[8-amino-6-(3-ethyl-1-methyl-6-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(25.5 mg, 22% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.528,[M+H]⁺=388.1, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.30 (s, 1H), 8.32 (s,1H), 7.58 (d, J=9.2 Hz, 1H), 6.96 (s, 1H), 6.64 (d, J=9.2 Hz, 1H), 6.56(s, 1H), 3.30 (s, 3H), 2.67-2.62 (m, 1H), 2.22-2.10 (m, 3H), 1.62-1.53(m, 2H), 1.3 (t, J=7.6 Hz, 3H).

Example 18(±)-cis-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 24)(±)-trans-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 25)

Step 1: 3-bromo-1,4-dimethyl-pyridin-2-one

To a mixture of 3-bromo-4-methyl-1H-pyridin-2-one (600 mg, 3.19 mmol)and K₂CO₃ (880 mg, 6.38 mmol) in acetonitrile (100 mL) was addediodomethane (905 mg, 6.38 mmol). The mixture was stirred overnight atroom temperature. The mixture was then filtered, concentrated andpurified by flash column chromatography (50% ethyl acetate in petroleumether) to afford 3-bromo-1,4-dimethyl-pyridin-2-one (570 mg, 88% yield)as a white solid. LCMS (ESI): [M+H]⁺=202.0.

Step 2:3-(3-amino-8-chloroisoquinolin-6-yl)-1,4-dimethylpyridin-2(1H)-one

To a sealed tube was added 3-bromo-1,4-dimethyl-pyridin-2-one (350 mg,1.73 mmol), (3-amino-8-chloro-6-isoquinolyl)boronic acid (462 mg, 2.08mmol), Pd(dppf)Cl₂ (141 mg, 0.19 mmol), K₃PO₄ (332 mg, 1.57 mmol),sodium acetate (387 mg, 4.72 mmol), acetonitrile (20 mL) and water (2mL). The mixture was bubbled through with N₂ for 2 minutes and stirredat 90° C. for 3 hours. The mixture was concentrated and purified byflash column chromatography (100% ethyl acetate) to give3-(3-amino-8-chloro-6-isoquinolyl)-1,4-dimethyl-pyridin-2-one (240 mg,43% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=300.1.

Step 3:(±)-cis-N-[8-chloro-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

To a cooled (0° C.) mixture of (±)-cis-2-fluorocyclopropanecarboxylicacid (83 mg, 0.80 mmol),3-(3-amino-8-chloro-6-isoquinolyl)-1,4-dimethyl-pyridin-2-one (200 mg,0.67 mmol) and pyridine (0.54 mL, 6.67 mmol) in dichloromethane (10 mL)was added POCl₃ (102 mg, 0.67 mmol). The mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated and purified byprep-TLC (petroleum ether/ethyl acetate=1/2) to give(±)-cis-N-[8-chloro-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(239 mg, 92% yield) as a gray solid. LCMS (ESI): [M+H]⁺=386.1.

Step 4:(±)-cis-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamideandtrans-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (668 mg, 5.7 mmol),Pd₂(dba)₃ (104 mg, 0.11 mmol), Cs₂CO₃ (557 mg, 1.71 mmol), Xantphos (110mg, 0.23 mmol),(±)-cis-N-[8-chloro-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(220 mg, 0.57 mmol), DMF (3 mL), and toluene (3 mL) in a glove box. Themixture was stirred at 110° C. for 18 hours. The mixture was taken up inethyl acetate (50 ml) and washed with brine. The organics were thenseparated, dried (Na₂SO₄), and concentrated to dryness. The crudeproduct was then purified by reverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(29.6 mg, 14% yield) as a yellow solid andtrans-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(13 mg, 6% yield) as a yellow solid.(±)-cis-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide:LCMS (ESI): R_(T) (min)=1.543, [M+H]⁺=367.1, method=C; ¹H NMR (400 MHz,CD₃OD) δ 9.21 (s, 1H), 8.28 (s, 1H), 7.58(d, J=6.8 Hz, 1H), 6.91 (s,1H), 6.58 (s, 1H), 6.40 (d, J=6.8 Hz, 1H), 4.98-4.78 (m, 1H), 3.59 (s,3H), 2.17-2.13 (m, 1H), 2.01 (s, 3H), 1.87-1.76 (m, 1H), 1.26-1.17 (m,1H).(±)-trans-N-[8-amino-6-(1,4-dimethyl-2-oxo-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide:LCMS (ESI): R_(T) (min)=1.524, [M+H]⁺=367.1, method=B; ¹H NMR (400 MHz,CD₃OD) δ 9.21 (s, 1H), 8.21 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 6.89 (s,1H), 6.58 (s, 1H), 6.40 (d, J=6.8 Hz, 1H), 4.97-4.78 (m, 1H), 3.59 (s,3H), 2.49-2.39 (m, 1H), 2.01 (s, 3H), 1.55-1.47 (m, 1H), 1.41-1.36 (m,1H).

Example 19(±)-cis-N-(8-amino-6-(6-methoxy-2-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 26)

Step 1:6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a sealed tube was added 3-bromo-6-methoxy-2-methyl-pyridine (1.2 g,5.94 mmol), bis(pinacolato)diboron (1.81 g, 7.13mmol), Pd(dppf)Cl₂ (434mg, 0.59 mmol), potassium acetate (1164 mg, 11.88 mmol) and 1,4-dioxane(10 mL). The mixture was stirred at 95° C. for 16 hours. The mixture wasthen concentrated and purified by prep-TLC (silica gel, petroleumether/ethyl acetate=15/1) to give2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.4 g, 94% yield) as a yellow oil. LCMS (ESI) [M+H]⁺=250.0.

Step 2:(±)-cis-N-(8-chloro-6-(6-methoxy-2-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(725 mg, 2.91mmol),(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(500 mg, 1.46 mmol), PdCl₂(dppf) (106 mg, 0.15 mmol), and K₂CO₃ (602 mg,4.37mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was purged 3 timeswith N₂. The mixture was stirred at 90° C. for 3 hours. Water (10 mL)was added. The mixture was extracted with ethyl acetate (10 mL×2). Theorganic layer was washed with water (20 mL×3) then brine(20 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byprep-TLC (silica gel, petroleum ether/ethyl acetate=3/1) to give(±)-cis-N-[8-chloro-6-(6-methoxy-2-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(370 mg, 66% yield) as white solid. LCMS (ESI) [M+H]⁺=386.0.

Step 3:(±)-cis-N-(8-amino-6-(6-methoxy-2-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (151 mg, 1.3mmol),Pd₂(dba)₃ (23 mg, 0.03 mmol), Cs₂CO₃(126 mg, 0.39 mmol), Xantphos (25mg, 0.05 mmol),(±)-cis-N-[8-chloro-6-(6-methoxy-2-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(50 mg, 0.13 mmol) and toluene (1 mL) in a glove box. The mixture wasstirred at 130° C. for 2 hours. Water (10 mL) was added. The mixture wasextracted with ethyl acetate (10 mL×2).The organic layer was washed withwater (20 mL×3), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (silica gel,dichloromethane/methanol=20/1) to give(±)-cis-N-[8-amino-6-(6-methoxy-2-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(13 mg, 27% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.738,[M+H]⁺=367.0. Method=G; ¹H NMR(400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.29 (s,1H), 7.59 (d, J=8.4 Hz, 1H), 6.98 (s, 1H), 6.71(d, J=8.0 Hz, 1H),6.69(d, J=1.6 Hz, 1H), 4.99-4.80 (m, 1H), 3.96 (s, 3H), 2.44 (s, 3H),2.18-2.14 (m, 1H), 1.86-1.79 (m, 1H), 1.25-1.22 (m, 1H).

Example 20(±)-cis-N-(8-amino-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 27)

A mixture of(±)-cis-N-[8-amino-6-(6-methoxy-2-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 0.27 mmol) in acetonitrile (4 mL) was added iodotrimethylsilane(0.04 mL, 0.27 mmol). The mixture was stirred at 90° C. for 1 hour.Water (10 mL) was added. The mixture was extracted with ethyl acetate(10 mL×2). The organic layer was washed with water (20 mL×3) then brine(20 mL), dried over Na₂SO₄, filtered and concentrated. The mixture waspurified with reverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(6-hydroxy-2-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(50 mg, 52% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.348,[M+H]⁺=353.0. Method=G; ¹H NMR(400 MHz, CD₃OD) δ 9.20(s, 1H), 8.29(s,1H), 7.62(d, J=9.2 Hz, 1H), 6.97(s, 1H), 6.65 (d, J=1.2 Hz, 1H), 6.48(d,J=9.2 Hz, 1H), 4.98-4.80 (m, 1H), 2.35(s, 3H), 2.18-2.13 (m, 1H),1.86-1.79 (m, 1H),1.24-1.20 (m, 1H).

Example 21(±)-cis-N-(8-amino-6-(5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 28)

Step 1:(±)-cis-N-(8-chloro-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(350 mg, 1.02 mmol),5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(386 mg, 1.32 mmol), Pd(dppf)Cl₂ (92 mg, 0.13 mmol), K₃PO₄ (214 mg, 1.02mmol) and sodium acetate (253 mg, 3.09 mmol), acetonitrile (20 mL) andwater (2 mL). The mixture was bubbled through with N₂ for 2 min andstirred at 90° C. for 3 hours. Water (10 mL) was added. The mixture wasextracted with ethyl acetate (10 mL×2).The organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by prep-TLC (silica gel, petroleum ether/ethyl acetate=2/1)to give(±)-cis-N-[8-chloro-6-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(350 mg, 80% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=429.7.

Step 2:(±)-cis-N-(8-amino-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (956 mg, 8.16 mmol),Pd₂(dba)₃ (149 mg, 0.16 mmol), Cs₂CO₃ (1.33 g, 4.08 mmol), Xantphos (158mg, 0.33 mmol),(±)-cis-N-[8-chloro-6-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(350 mg, 0.82 mmol) and toluene (5 mL) in a glove box. The mixture wasstirred at 110° C. for 2 hours. Water (10 mL) was added. The mixture wasextracted with ethyl acetate (10 mL×2). The organic layer was washedwith water (20 mL×3) then brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give crude product(±)-cis-N-[8-amino-6-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(0.3 g, 90% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=410.7.

Step 3:(±)-cis-N-(8-amino-6-(5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a mixture of(±)-cis-N-[8-amino-6-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(200 mg, 0.49 mmol) in THF (3 mL) was added HCl in 1,4-dioxane (4 M in1,4-dioxane, 8 mL, 32 mmol). The mixture was stirred at room temperaturefor 16 hours. The mixture was concentrated. A 7 M of NH₃ in methanolsolution was added to adjust the pH of the mixture to 8. The mixture wasconcentrated and purified by reverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(5-methyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(20 mg, 12.6% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.417,[M+H]⁺=326.7. Method=G; ¹H NMR(400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.27 (s,1H), 7.81(s, 1H), 7.14 (s, 1H), 6.90 (d, J=1.6 Hz, 1H), 4.99-4.79 (m,1H), 2.52 (s, 3H), 2.19-2.12 (m, 1H), 1.87-1.79 (m, 1H), 1.25-1.20 (m,1H).

Example 22(1S,2S)—N-(8-amino-6-(5-oxopyrrolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 30)

To a sealed tube was added tert-butyl carbamate (202 mg, 1.73 mmol),Pd₂(dba)₃ (31 mg, 0.03 mmol), Cs₂CO₃ (168 mg, 0.52 mmol), xantphos (33mg, 0.07 mmol),(1S,2S)—N-[8-chloro-6-(6-methoxy-2-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(10 mg, 0.03 mmol), DMF (0.5 mL) and toluene (0.5 mL) in glove box. Themixture was stirred at 110° C. for 16 hours. Water (10 mL) was added.The mixture was extracted with ethyl acetate (10 mL×2). The organicextracts were washed with water (20 mL×3) then brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The mixture was purified by reversephase prep-HPLC to give(1S,2S)—N-[8-amino-6-(5-oxopyrrolidin-3-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(10 mg, 17% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.401,[M+H]⁺=329.7. Method=C; ¹H NMR(400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.24 (s,1H), 6.99 (s, 1H), 6.69 (s, 1H), 4.99-4.78 (m, 1H), 3.86-3.76 (m, 2H),3.51-3.47 (m, 1H), 2.81-2.74 (m, 1H), 2.59-2.53 (m, 1H), 2.14-2.11(m,1H), 1.79-1.73 (m, 1H), 1.22-1.20 (m, 1H).

Example 23(±)-cis-N-(8-amino-6-(4-ethyl-6-(hydroxymethyl)pyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 31)

Step 1: (±)-methyl5-(8-chloro-3-(cis-2-fluorocyclopropanecarboxamido)isoquinolin-6-yl)-4-ethylpicolinate

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(130 mg, 0.38 mmol), methyl4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate(227 mg, 0.78 mmol), Pd(dppf)Cl₂ (26 mg, 0.04 mmol), K₂CO₃ (156 mg,1.14mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was purged 3 timeswith N₂. The mixture was stirred at 90° C. for 2 hours. Water (10 mL)was added. The mixture was extracted with ethyl acetate (10 mL×2). Thecombined extracts were washed with water and then brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-TLC(silica gel, petroleum ether/ethyl acetate=2/1) to give (±)-methyl5-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-ethyl-pyridine-2-carboxylate(150 mg, 92% yield) as a yellow oil. LCMS (ESI) [M+I-I]⁺=428.7.

Step 2: (±)-methyl5-(8-amino-3-(cis-2-fluorocyclopropanecarboxamido)isoquinolin-6-yl)-4-ethylpicolinate

To a sealed tube was added tert-butyl carbamate (410 mg, 3.51 mmol),Pd₂(dba)₃ (64 mg, 0.07 mmol), Cs₂CO₃ (342 mg, 1.05 mmol), Xantphos (67mg, 0.1400 mmol), (±)-methyl5-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-ethyl-pyridine-2-carboxylate(150 mg, 0.35 mmol) toluene (1 mL) and DMF (1 mL) in glove box. Themixture was stirred at 130° C. for 2 hours. Water (10 mL) was added. Themixture was extracted with ethyl acetate (10 mL×2). The organic layerwas washed with water (20 mL×3), brine (20 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC (silicagel, dichloromethane/methanol, 20/1) to give (±)-methyl5-[8-amino-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-ethyl-pyridine-2-carboxylate(60 mg, 42% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=409.7.

Step 3:(±)-cis-N-(8-amino-6-(4-ethyl-6-(hydroxymethyl)pyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a mixture of (±)-methyl5-[8-amino-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-ethyl-pyridine-2-carboxylate(60 mg, 0.15 mmol) in methyl alcohol (5 mL) was added NaBH₄ (111 mg,2.94 mmol) at 0° C. The mixture was stirred at room temperature for 5hours. Water (2 mL) was added to quench the reaction. The mixture wasconcentrated and re-suspended in a solution of dichloromethane andmethanol (10:1, 10 mL). The mixture was filtered and washed with asolution of dichloromethane and methanol (10:1).The filtrated wasconcentrated and purified by reverse phase rep-HPLC to give(±)-cis-N-[8-amino-6-[4-ethyl-6-(hydroxymethyl)-3-pyridyl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(12 mg, 21% yield) as a yellow solid. LCMS (ESI) RT (min)=1.565,[M+H]⁺=381.7. Method=C; ¹H NMR(400 MHz, CD3OD) δ 9.25 (s, 1H), 8.31(s,1H), 8.30 (s, 1H) 7.56 (s, 1H), 6.99 (s, 1H), 6.67(d, J=1.6 Hz,1H),4.98-4.75 (m, 1H), 4.75 (s, 2H), 2.74 (q, J=7.2 Hz, 2H), 2.18-2.15 (m,1H), 1.88-1.85 (m, 1H), 1.23-1.20 (m, 1H), 1.18 (t, J=7.2 Hz, 3H).

Example 24(±)-trans-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 32)

The compound was synthesized using a method similar to those describedherein. The LC/MS and NMR data are shown in Table A-1.

Example 25(1S,2S)—N-(8-amino-6-(4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (Compound 37)

Step 1: 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (1 g, 3.88 mmol) and(1S,2S)-2-fluorocyclopropanecarboxylic acid (0.49 g, 4.66 mmol) indichloromethane (10 mL) and pyridine (0.5 mL) was stirred at 0° C. for0.5 hours before the addition of POCl₃ (0.4 mL, 4.29 mmol). The reactionwas then stirred at room temperature for 1 hour. The reaction mixturewas diluted with ethyl acetate (10 mL) and pH adjusted to 7-8 withsaturated NaHCO₃. The organic layer was then separated, dried (NaSO₄)and concentrated to dryness. The residue was purified with silica-gelcolumn chromatography (petroleum ether:ethyl acetate, 1:1) to give thetitle compound (1 g, 62.5% yield). LCMS (ESI) [M+H]⁺=345.0.

Step 2:(1S,2S)—N-(8-chloro-6-(4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(1S,2S)—N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(150 mg, 0.44 mmol), 4-methyloxazolidin-2-one (53 mg, 0.52 mmol),Xanphos (25 mg, 0.04 mmol), Pd₂(dba)₃ (40 mg, 0.04 mmol) and K₃PO₄ (277mg, 1.31 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 3 hours.The reaction was concentrated to dryness. The residue was purified withsilica-gel column chromatography (petroleum ether/ethyl acetate=1:1 topetroleum ether/ethyl acetate=1:2) to give the title compound as ayellow solid (140 mg, 61% yield). LCMS (ESI) [M+H]⁺=364.1.

Step 3: tert-butyl3-((1S,2S)-2-fluorocyclopropanecarboxamido)-6-(4-methyl-2-oxooxazolidin-3-yl)isoquinolin-8-ylcarbamate

A mixture of tert-butyl carbamate (241 mg, 2.06 mmol),(1S,2S)—N-[8-chloro-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(150 mg, 0.41 mmol), Pd₂(dba)₃ (74 mg, 0.08 mmol), Brettphos (44 mg,0.08 mmol), and tBuONa (118 mg, 1.23 mmol) in 1,4-dioxane (3 mL) wasstirred under Ar at 90° C. for 6 hours. The reaction was concentrated todryness. The residue was purified by silica-gel column chromatography(petroleum ether:ethyl acetate=2:1 to petroleum ether:ethyl acetate=1:1)to give the title compound as a yellow solid (70 mg, 14.8% yield). LCMS(ESI) [M+H]⁺=445.2.

Step 4:(1S,2S)—N-(8-amino-6-(4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-6-(4-methyl-2-oxo-oxazolidin-3-yl)-8-isoquinolyl]carbamate(70 mg, 0.16 mmol) in HCl in 1,4-dioxane (1 mL, 4 M) was stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness. Theresidue was taken up in methanol (2 mL) and adjusted pH to 7-8 with satNaHCO₃. The mixture was purified by reverse phase prep-HPLC to give thetitle compound as a brown solid. LCMS (ESI): R_(T)(min)=1.54,[M+H]⁺=345.1, method=C.¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (s, 1H), 9.19(s, 1H), 8.19 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.92 (d, J=1.6 Hz, 1H),6.32 (s, 2H), 5.01-4.83 (m, 1H), 4.71-4.68 (m, 1H), 4.58-4.54 (m, 1H),4.06-4.03 (m, 1H), 2.28-2.21 (m, 1H), 1.71-1.61 (m, 1H), 1.29 (d, J=6.0Hz, 3H), 1.19-1.12 (m, 1H).

Example 26(±)-trans-N-(8-amino-6-(quinolin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 38)

Step 1: quinolin-4-ylboronic acid

A mixture of 4-bromoquinoline (1.0 g, 4.81 mmol), bis(pinacolato)diboron(12.0 g, 47.26 mmol), PdCl₂dppf (0.7 g, 0.96 mmol), potassium acetate(1.4 g, 14.29 mmol) in 1,4-dioxane (100 mL) was stirred under Ar at 80°C. for 2 hours. The reaction was concentrated to dryness. The residuewas purified by silica-gel column chromatography (petroleum ether/ethylacetate=1:1 to dichloromethane:methanol=1:1) to give the title compoundas a yellow solid (2 g, crude). LCMS (ESI) [M+I-1]⁺=256.1.

Step 2:(±)-trans-N-(8-chloro-6-(quinolin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(800 mg, 2.28 mmol), quinoline-4-boronic acid (100 mg, 0.58 mmol),Pd(PPh₃)₄ (67 mg, 0.06 mmol), and K₂CO₃ (239 mg, 1.73 mmol) in1,4-dioxane (4 mL) and water (1 mL) was stirred under Ar at 90° C. for 3hours. The reaction was concentrated to dryness. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=4:1 to petroleum ether/acetate=2:1) to give the title compoundas a yellow solid (100 mg, 25.3% yield). LCMS (ESI) [M+H]⁺=399.1.

Step 3:(±)-trans-2-cyano-N-(8-(diphenylmethyleneamino)-6-(quinolin-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture oftrans-N-[8-chloro-6-(4-quinolyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(90 mg, 0.23 mmol), benzophenone imine (123 mg, 0.68 mmol), Pd₂(dba)₃(41 mg, 0.04 mmol), Xantphos (13 mg, 0.02 mmol), and Cs₂CO₃ (220 mg,0.67 mmol) in DMF (3 mL) and toluene (1 mL) was heated in a microwavereactor at 150° C. for 1 hour. The reaction was diluted with ethylacetate and washed with brine. The organic extract was then separated,dried (Na₂SO₄) and concentrated to dryness. The residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=4:1) togive the title compound as a yellow solid (40 mg, 33% yield). LCMS (ESI)[M+H]⁺=544.2.

Step 4:(±)-trans-N-(8-amino-6-(quinolin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-quinolyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(40 mg, 0.07 mmol), and TFA (0.5 mL, 6.71 mmol) in dichloromethane (2mL) and two drops of water was stirred at room temperature for 3 hours.The reaction was concentrated to dryness. The residue was taken up inethyl acetate (10 mL) and adjusted pH to 7-8 with saturated aqueousNaHCO_(3.) The mixture was concentrated to dryness and purified bysilica gel column chromatography (ethyl acetate/petroleum ether=2:1 toethyl acetate) to give the title compound as a yellow solid (18.5 mg,64% yield). LCMS (ESI) R_(T) (min)=1.573, [M+H]⁺=380.1, method=B. ¹H NMR(400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.41 (s, 1H), 8.96 (d, J=4.4 Hz,1H), 8.28 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),7.82-7.78 (m, 1H), 7.62-7.58 (m, 1H), 7.51 (d, J=4.4 Hz, 1H), 7.07 (s,1H), 6.73 (d, J=1.6Hz, 1H), 6.49 (s, 2H), 2.77-2.72 (m, 1H), 2.15-2.11(m, 1H), 1.60-1.58 (m, 1H), 1.45-1.40 (m, 1H).

Example 27(±)-cis-N-(8-amino-6-(5-amino-4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 39)

Step 1: 3,5-dibromo-4-ethylpyridine

To a solution of diisopropylamine (3.5 mL, 24.8 mmol) in THF (50 mL) wasadded n-BuLi (2.5 M in hexane, 10.5 mL, 26.25 mmol) in portions at −78°C. The mixture was stirred at room temperature for 15 minutes. To thereaction mixture was then added 3,5-dibromopyridine (5.0 g, 21.11 mmol)at −78° C. under N₂. After 1 h of stirring at −78° C., iodoethane (3.29g, 21.11 mmol) was added at −78° C. The mixture was then stirred at roomtemperature for 16 hours. The reaction was then washed with a saturatedsolution of NH₄Cl (100 mL). The organics were then separated, dried(Na₂SO₄) and concentrated to dryness. The residue was purified bysilica-gel column chromatography (petroleum ether/ethyl acetate=20:1) togive the title compound as a yellow solid. LCMS (ESI) [M+H]⁺=265.9.

Step 2: tert-butyl 5-bromo-4-ethylpyridin-3-ylcarbamate

A mixture of 3,5-dibromo-4-ethyl-pyridine (2.4 g, 9.06 mmol), tert-butylcarbamate (1.0 g, 8.54 mmol), K₂CO₃ (2.5 g, 18.12 mmol), CuI (0.86 g,4.53 mmol), and N1,N2-dimethylethane-1,2-diamine (0.4 g, 4.55 mmol) in1,4-dioxane (60 mL) was stirred under Ar at 100° C. for 4 hours. Thereaction was filtered and concentrated to dryness. The residue waspurified by silica-gel column chromatography (petroleum ether/ethylacetate=10:1 to petroleum ether/ethyl acetate=4:1) to give the titlecompound as a white solid (1.01 g, 37% yield). LCMS (ESI) [M+H]⁺=301.0.

Step 3: tert-butyl4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ylcarbamate

A mixture of bis(pinacolato)diboron (1.26 g, 4.98 mmol), tert-butylN-(5-bromo-4-ethyl-3-pyridyl)carbamate (1.0 g, 3.32 mmol), PdCl₂dppf(0.24 g, 0.33 mmol), and potassium acetate (0.98 g, 9.96 mmol) in1,4-dioxane (20 mL) was stirred under Ar at 90° C. for 3 hours. Thereaction was concentrated to dryness and purified by silica-gel columnchromatography (ethyl acetate) to give the title compound as a black oil(490 mg, 25% yield). LCMS (ESI) [M+H]⁺=349.3.

Step 4: (±)-tert-butyl5-(8-chloro-3-((cis)-2-fluorocyclopropanecarboxamido)isoquinolin-6-yl)-4-ethylpyridin-3-ylcarbamate

A mixture of (±)-tert-butylN-[4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]carbamate(250 mg, 0.72 mmol),cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(150 mg, 0.44 mmol), PdCl₂dppf (52 mg, 0.07 mmol), K₃PO₄ (304 mg, 1.43mmol) and sodium acetate (117 mg, 1.43 mmol) in acetonitrile (4 mL) andwater (1 mL) was stirred under Ar at 90° C. for 3 hours. The reactionwas concentrated to dryness. The residue was then purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate=4:1 to petroleumether/ethyl acetate=1:1) to give the title compound as a yellow solid(70 mg, 20.1% yield). LCMS (ESI) [M+H]⁺=485.2.

Step 5: (±)-tert-butylN-[6-[5-(tert-butoxycarbonylamino)-4-ethyl-3-pyridyl]-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-8-isoquinolyl]carbamate

A mixture of tert-butylN-[5-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-ethyl-3-pyridyl]carbamate(40 mg, 0.08 mmol), tert-butyl carbamate (96 mg, 0.82 mmol), Pd₂(dba)₃(8 mg, 0.01 mmol), Brettphos (5 mg, 0.01 mmol), and tBuONa (23 mg, 0.24mmol) in 1,4-dioxane (2 mL) was heated under Ar at 90° C. for 1 hour.The reaction was concentrated to dryness. The residue was purified bysilica-gel column chromatography (petroleum ether/ethyl acetate=1:1 toethyl acetate/petroleum ether=2:1) to give the title compound as ayellow solid (20 mg, 34.7% yield). LCMS (ESI) [M+H]⁺=566.3.

Step 6:(±)-cis-N-(8-amino-6-(5-amino-4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of (±)-tert-butylN-[6-[5-(tert-butoxycarbonylamino)-4-ethyl-3-pyridyl]-3-[[(cis)-2-fluorocyclopropanecarbonyl]amino]-8-isoquinolyl]carbamate(20 mg, 0.04 mmol) in a solution of HCl in 1,4-dioxane (1 mL, 4 M) wasstirred at room temperature for 1 hour. The reaction was concentrated todryness. The residue was taken up in methanol (2 ml) and adjusted pH to7-8 with saturated NaHCO_(3.) The mixture was purified by reverse phaseprep-HPLC (5-95% methanol and 1% NH₄HCO₃ in water) to give the titlecompound as a yellow solid (11.6 mg, 83.5% yield). LCMS (ESI):R_(T)(min)=1.54, [M+H]⁺=366.2, method=F. ¹H NMR (400 MHz, DMSO-d₆) δ10.80 (s, 1H), 9.30 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H),6.79 (s, 1H), 6.48 (s, 1H), 6.31 (s, 2H), 5.21 (s, 2H), 5.02-4.84 (m,1H), 2.46-2.41 (m, 2H), 2.27-2.24 (m, 1H), 1.69-1.62 (m, 1H), 1.18-1.14(m, 1H), 0.98 (t, J=7.6 Hz, 3H).

Example 283-amino-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)propanamide(Compound 40)

Step 1: tert-butyl3-(6-bromo-8-chloroisoquinolin-3-ylamino)-3-oxopropylcarbamate

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (150 mg, 0.58 mmol),3-(tert-butoxycarbonylamino)propanoic acid (165 mg, 0.87 mmol) indichloromethane (2 mL) and pyridine (0.5 mL) was stirred at 0° C. for0.5 hours. POCl₃ (89 mg, 0.58 mmol) was added to the reaction mixture,then the mixture was stirred at room temperature for 1 hour. Thereaction mixture was washed with 10 mL water and pH adjusted to 7-8 withsaturated aqueous NaHCO₃. The organic layer was then separated and dried(NaSO₄) before concentration to dryness. The residue was purified withsilica-gel column chromatography (petroleum ether/ethyl acetate=4:1 topetroleum ether/ethyl acetate=2:1) to give the title compound as ayellow solid (200 mg, 70% yield). LCMS (ESI) [M+H]⁺=430.0.

Step 2: tert-butyl3-(8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-3-oxopropylcarbamate

A mixture of tert-butylN-[3-[(6-bromo-8-chloro-3-isoquinolyl)amino]-3-oxo-propyl]carbamate (195mg, 0.45 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120mg, 0.55 mmol), Pd(PPh₃)₄ (53 mg, 0.05 mmol), and K₂CO₃ (188 mg, 1.36mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated under Ar at 90°C. for 3 hours. The reaction was concentrated to dryness. The residuewas purified with silica-gel column chromatography (petroleumether/ethyl acetate=1:1 to 100% ethyl acetate) to give the titlecompound as a yellow solid (190 mg, 59% yield). LCMS (ESI) [M+H]⁺=441.2.

Step 3: tert-butyl3-(3-aminopropanamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of tert-butyl carbamate (470 mg, 4.01 mmol), tert-butylN-[3-[[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-3-oxo-propyl]carbamate(180 mg, 0.41 mmol), Cs₂CO₃ (398 mg, 1.22 mmol), Pd₂(dba)₃ (37 mg, 0.04mmol), and Brettphos (21 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was heatedunder Ar at 90° C. for 3 hours. The reaction was concentrated todryness. The residue was purified with silica-gel column chromatography(petroleum ether/ethyl acetate=1:1 to ethyl acetate/petroleum ether=2:1)to give the title compound as a yellow solid (150 mg, 38% yield). LCMS(ESI) [M+H]⁺=522.3.

Step 4:3-amino-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)propanamide

A mixture of tert-butylN-[3-[[8-(tert-butoxycarbonylamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-3-oxo-propyl]carbamate(150 mg, 0.29 mmol) in HCl in 1,4-dioxane (4.0 M, 2 mL, 8 mmol) wasstirred at room temperature for 1 hour. The reaction was concentrated todryness and the residue was taken up in methanol (2 mL) and adjusted pHto 7-8 with sat NaHCO₃. The mixture was purified directly with reversephase prep-HPLC (5-95% methanol and 1% NH₄HCO₃) to give the titlecompound as a yellow solid (39.5 mg). LCMS (ESI): R_(T)(min)=1.45,[M+H]⁺=322.2, method=F. ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 8.40 (d,J=5.2 Hz, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.39 (d, J=5.2 Hz, 1H), 6.99(s, 1H), 6.68 (d, J=1.2 Hz, 1H), 3.05 (t, J=6.8 Hz, 2H), 2.66 (t, J=6.8Hz, 2H), 2.37 (s, 3H).

Example 29 (±)-cis-N-(8-amino-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluoro cyclopropanecarboxamide (Compound 41)

Step 1:5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-bromo-3-isopropyl-1H-pyrazole (2.0 g, 10.58 mmol),Pd(dppf)Cl₂ (1.0 g, 1.37 mmol), potassium acetate (4.8 g, 48.98 mmol),bis(pinacolato)diboron (25.0 g, 98.45 mmol) in 1,4-dioxane (100 mL) wasstirred overnight under Ar at 100° C. The reaction was concentrated todryness and the crude was then purified by silica gel columnchromatography (ethyl acetate/petroleum ether, 1/10 to 1/1) to afford3-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.28 g, 39% yield) as a yellow liquid. LCMS(ESI):[M+H]⁺=237.2.

Step 2: (±)-cis-N-(8-chloro-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A pressure tube containing the reaction mixture of3-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(600 mg, 1.91 mmol), Pd(dppf)Cl₂ (100 mg, 0.14 mmol), K₂CO₃ (560 mg,4.06 mmol),(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(520 mg, 1.51 mmol), 1,4-dioxane (10 mL) and water (1.5 mL) was heatedin a microwave reactor at 130° C. for 80 minutes. The reaction wasconcentrated to dryness and the crude was then purified by silica gelcolumn chromatography (ethyl acetate) to afford(±)-cis-N-[8-chloro-6-(3-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(220 mg, 37% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=373.1.

Step 3:(±)-cis-N-(8-chloro-6-(5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A solution of(±)-cis-N-[8-chloro-6-(5-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(220 mg, 0.59 mmol), 3,4-dihydro-2h-pyran (2.0 mL, 21.92 mmol), TFA (0.5mL, 6.71 mmol) in dichloromethane (15 mL) was heated overnight atreflux. The reaction was concentrated to dryness and the crude was thenpurified by silica gel column chromatography (ethyl acetate/petroleumether, 1/4 to 1/1) to afford(±)-cis-N-[8-chloro-6-(5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(230 mg, 84% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=457.2.

Step 4:(±)-cis-N-[8-(benzhydrylideneamino)-6-(3-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamideand(±)-trans-N-[8-(benzhydrylideneamino)-6-(3-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.2 mmol), benzophenone imine (182 mg, 1.0 mmol), Xantphos (58mg, 0.1 mmol), Pd₂(dba)₃ (46 mg, 0.05 mmol), and Cs₂CO₃ (170 mg, 0.52mmol) in dry DMF(3.0 mL) and dry toluene (3.0 mL) was stirred at 130° C.under an Ar atmosphere for 4 hours. The reaction was concentrated. Theresidue was taken up in ethyl acetate (15 ml) and washed with 20 mL ofbrine. The organic layer was then separated, dried (Na₂SO₄) andconcentrated to dryness. The crude was then purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether, 1:3 to 1:1) toafford(±)-cis-N-[8-(benzhydrylideneamino)-6-(3-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(77 mg, 61% yield) as a yellow liquid (LCMS(ESI):[M+H]⁺=602.3) and(±)-trans-N-[8-(benzhydrylideneamino)-6-(3-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(43mg, 32% yield) as yellow solid (LCMS (ESI): [M+H]⁺=602.3).

Step 5: (±)-cis-N-(8-amino-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A solution of(±)-cis-N-[8-(benzhydrylideneamino)-6-(3-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(120.0 mg, 0.20 mmol) in HCl in 1,4-dioxane (2.0 mL, 4 M, 8 mmol) wasstirred at room temperature for 1 hour. The reaction was concentratedand the resulting residue was purified by reverse phase prep-HPLC(methanol 0-40/0.1% HCl in water) to afford(±)-cis-N-[8-amino-6-(3-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(30 mg, 43% yield) as a red solid (HCl salt). LCMS(ESI): [M+H]⁺=354.2,R_(T)(min)=1.53, method=B; ¹HNMR (400 MHz,CD₃OD) δ 9.43 (s, 1H), 8.39(s, 1H), 7.70 (s, 1H), 7.29 (s, 1H), 7.03 (s, 1H), 5.10-5.06 (m, 1H),3.62-3.57 (m, 1H), 2.20-2.17(m, 1H), 1.99-1.89(m, 1H), 1.42 (d, J=6.8Hz, 6H), 1.39-1.30(m, 1H).

Example 30 (±)-trans-N-(8-amino-6-(5-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluoro cyclopropanecarboxamide (Compound 42)

A solution of(±)-trans-N-[8-(benzhydrylideneamino)-6-(3-isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(115 mg, 0.19 mmol) in a HCl in 1,4-dioxane solution (2.0 mL, 4 M, 8mmol) was stirred at room temperature for 1 hour. The reaction wasconcentrated and the resulting residue was purified by reverse phaseprep-HPLC (methanol 0-50/0.1% HCl in water) to afford(±)-trans-N-[8-amino-6-(3-isopropyl-1H-pyrazol-4-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(45 mg, 65% yield) as a red solid (HCl salt). LCMS(ESI): [M+H]⁺=354.2,R_(T)(min)=1.59, method=B; ¹H NMR (400 MHz,CD₃OD) δ 9.41 (s, 1H), 8.37(s, 1H), 7.68 (s, 1H), 7.30 (s, 1H), 7.03 (s, 1H), 5.08-5.05 (m, 1H),3.62-3.58 (m, 1H), 2.46-2.38 (m, 1H), 1.75-1.65 (m, 1H), 1.58-1.50 (m,1H), 1.42 (d, J=6.8 Hz, 6H).

Example 31(±)-cis-N-(8-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 43)

Step 1:methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-1-methyl-pyridin-2-one (500 mg, 2.66 mmol),bis(pinacolato)diboron (675 mg, 2.66 mmol), Pd(dppf)Cl₂ (97 mg, 0.13mmol) and potassium acetate (781 mg, 7.98 mmol) in 1,4-dioxane (20 mL)was heated at 100° C. for 12 hours. The mixture was diluted with ethylacetate (50 mL), filtered and concentrated to give crude product1-methyl-6-oxo-1,6-dihydropyridin-2-ylboronic acid (320 mg) as a greysolid, which was used in the next step without further purification.LCMS (ESI): [M+H]⁺=154.1.

Step 2:(±)-cis-N-(8-chloro-6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added (1-methyl-6-oxo-2-pyridyl)boronic acid (106mg, 0.70 mmol),(±)-cis-N-(6-bromo-8-chloroisoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(160 mg, 0.47 mmol), Pd(dppf)₂Cl₂ (42 mg, 0.06 mmol), K₃PO₄ (98 mg, 0.47mmol), sodium acetate (116 mg, 1.41 mmol), acetonitrile (20 mL) andwater (2 mL). The mixture was bubbled through with nitrogen for 2 minand then stirred at 90° C. for 3 hours. The mixture was concentrated andpurified by prep-TLC (petroleum ether/ethyl acetate, 1/2) to give(±)-cis-N-(8-chloro-6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(50 mg, 28% yield) as a white solid. LCMS (ESI): [M+H]⁺=372.0.

Step 3:(±)-cis-N-(8-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (157 mg, 1.34 mmol),Pd₂(dba)₃ (24 mg, 0.03 mmol), Cs₂CO₃ (131 mg, 0.40 mmol), Xantphos (26mg, 0.05 mmol),(±)-cis-N-(8-chloro-6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(50 mg, 0.13 mmol), DMF(2 mL), and toluene (2 mL) in a glove box. Themixture was stirred at 110° C. for 18 hours. The mixture wasconcentrated and purified by reverse phase prep-HPLC to give(±)-cis-N-(8-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(7 mg, 15% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.385,[M+H]⁺=353.1, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.27 (s, 1H), 8.36 (s,1H), 7.59 (dd, J=6.8, 9.2 Hz, 1H), 7.09 (s, 1H), 6.67 (d, J=1.6 Hz, 1H),6.62(dd, J=1.2, 9.2 Hz, 1H), 6.42 (dd, J=1.2, 6.8 Hz, 1H), 4.99-4.79 (m,1H), 3.46 (s, 3H), 2.19-2.13 (m, 1H), 1.87-1.78 (m, 1H), 1.27-1.18 (m,1H).

Example 32(±)-trans-N-[8-amino-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 44)

Step 1:methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 5-bromo-6-methyl-1h-indazole (400 mg, 1.9 mmol),bis(pinacolato)diboron (2.41g, 9.48 mmol), Pd(dppf)Cl₂ (277 mg, 0.38mmol), and potassium acetate (557 mg, 5.69 mmol) in DMF (10 mL) washeated to 90° C. for 3 hours under nitrogen. The mixture wasconcentrated and purified by prep-TLC (petroleum ether) to give6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(370 mg, 37% yield) as yellow oil. LCMS (ESI): [M+H]⁺=259.1.

Step 2:(±)-trans-N-(8-chloro-6-(6-methyl-1H-indazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a sealed tube was addedtrans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(160 mg, 0.46 mmol),6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(141 mg, 0.55 mmol), Pd(dppf)₂Cl₂ (41 mg, 0.06 mmol), sodium acetate(113 mg, 1.39 mmol), acetonitrile (2 mL) and water (0.2 mL). The mixturewas bubbled through with nitrogen for 2 min and then stirred at 100° C.for 3 hours. The mixture was concentrated and purified by prep-TLC(petroleum ether/ethyl acetate=2/1) to give(±)-trans-N-[8-chloro-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(160 mg, 82% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=402.1.

Step 3:(±)-trans-N-[8-chloro-6-(6-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a cooled (0° C.) suspension oftrans-N-[8-chloro-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(190 mg, 0.47 mmol) and p-toluenesulfonic acid (8 mg, 0.05 mmol) indichloromethane (5 mL) was added 3,4-dihydro-2h-pyran (47 mg, 0.57mmol). The reaction mixture was stirred at room temperature for 16hours. The mixture was concentrated and purified by prep-TLC (petroleumether/ethyl acetate, 4:1) to affordtrans-N-[8-chloro-6-(6-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(190 mg, 75% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=486.2.

Step 4:(±)-trans-2-cyano-N-(8-(diphenylmethyleneamino)-6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide

To a sealed tube was added benzophenone imine (61 mg, 0.34 mmol),trans-N-[8-chloro-6-(6-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(150 mg, 0.31mmol), Pd(OAc)₂ (7 mg, 0.03 mmol), Cs₂CO₃ (201 mg, 0.62mmol), xantphos (15 mg, 0.03 mmol) and toluene (5 mL). The mixture wasstirred at 145° C. for 16 hours. The reaction mixture was concentratedand purified by prep-TLC (petroleum ether/ethyl acetate, 1/2) to give(±)-trans-2-cyano-N-(8-(diphenylmethyleneamino)-6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide(90 mg, 46% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=631.1.

Step 5:(±)-trans-N-[8-amino-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-(6-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(80 mg, 0.13 mmol) in THF (3 mL) was added a HCl in 1,4-dioxane solution(2 mL, 4 M, 8 mmol). The mixture was stirred at room temperature for 1hour. The mixture was concentrated and purified by reverse phaseprep-HPLC to give(±)-trans-N-[8-amino-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(6.3 mg, 12.9% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.513,[M+H]⁺=383.1, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 8.27 (s,1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 6.76 (d,J=1.2 Hz, 1H), 2.65-2.64 (m, 1H), 2.39 (s, 3H), 2.14-2.09 (m, 1H),1.62-1.55 (m, 2H).

Example 33(±)-trans-N1-[8-amino-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]cyclopropane-1,2-dicarboxamide(Compound 45)

To a mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-(6-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(80 mg, 0.13 mmol) in THF (3 mL) was added a HCl in 1,4-dioxane solution(2 mL, 4 M, 8 mmol). The mixture was stirred at room temperature for 1hour. The mixture was concentrated and purified by reverse phaseprep-HPLC to give(±)-trans-N1-[8-amino-6-(6-methyl-1H-indazol-5-yl)-3-isoquinolyl]cyclopropane-1,2-dicarboxamide(8.3 mg, 16% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.372,[M+H]⁺=401.1, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 8.25 (s,1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 6.75 (s,1H), 2.42-2.38 (m, 4H), 2.25-2.20 (m, 1H), 1.44-1.40 (m, 2H).

Example 34(±)-cis-N-(8-amino-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (Compound 46)

(±)-trans-N-(8-amino-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 47)

Step 1:(±)-8-chloro-3-(cis-2-fluorocyclopropanecarboxamido)isoquinolin-6-ylboronicacid

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(1.0 g, 2.91 mmol), bis(pinacolato)diboron (960 mg, 3.78 mmol),Pd(dppf)Cl₂ (424 mg, 0.58 mmol), and potassium acetate (855 mg, 8.73mmol) in DMF (4 mL) was purged three times with N₂. The mixture wasstirred at 100° C. for 1 hour. The mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bysilica gel flash chromatography (petroleum ether/ethyl acetate, 3:1) togive8-chloro-3-(cis-2-fluorocyclopropanecarboxamido)isoquinolin-6-ylboronicacid (600 mg, 66% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=309.0.

Step 2:(±)-cis-N-(8-chloro-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added(±)-[8-chloro-3-[[cis-2-fluorocyclopropanecarbonyl]amino]-6-isoquinolyl]boronicacid (200 mg, 0.57 mmol), 3-bromo-4-methoxy-pyridine (128 mg, 0.68mmol), Pd(dppf)₂Cl₂ (51 mg, 0.07 mmol), K₃PO₄ (120 mg, 0.57 mmol),sodium acetate (142 mg, 1.73 mmol), 1,4-dioxane (2 mL) and water (0.2mL). The mixture was bubbled through with N₂ for 2 minutes and stirredat 100° C. for 3 hours. The mixture was concentrated and purified byprep-TLC (petroleum ether/ethyl acetate, 2/1) to give(±)-cis-N-(8-chloro-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(80 mg, 36% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=372.1.

Step 3:(±)-cis-N-(8-(diphenylmethyleneamino)-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added(±)-cis-N-[8-chloro-6-(4-methoxy-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(60 mg, 0.16 mmol), benzophenone imine (32 mg, 0.18 mmol), Pd(OAc)₂ (4mg, 0.02 mmol), Cs₂CO₃ (105 mg, 0.32 mmol), Xantphos (8 mg, 0.02 mmol),DMF (1 mL) and toluene (3 mL). The mixture was heated in a microwavereactor at 145° C. for 30 minutes. The reaction was diluted with ethylacetate (50 mL), washed with brine, dried (Na₂SO₄) and concentrated. Thecrude product was then purified by flash silica gel columnchromatography (80% ethyl acetate in hexane) to give a mixture of(±)-cis-N-(8-(diphenylmethyleneamino)-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamideand(±)-trans-N-(8-(diphenylmethyleneamino)-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(20 mg, 24% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=517.2.

Step 4:(±)-cis-N-(8-amino-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a solution of mixture of(±)-cis-N-(8-(diphenylmethyleneamino)-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamideandtrans-N-(8-(diphenylmethyleneamino)-6-(4-methoxypyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(20 mg, 0.04 mmol) in THF (3 mL) was added a solution of HCl in1,4-dioxane (2 mL, 4 M, 8 mmol). The mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated and purified byreverse phase prep-HPLC to give the two desired isomers:(±)-cis-N-[8-amino-6-(4-methoxy-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(4.9 mg, 36%, yellow solid). LCMS (ESI): R_(T) (min)=1.253,[M+H]⁺=353.1, method=A; ¹H NMR (400 MHz,CD₃OD): δ 9.22 (s, 1H), 8.44 (d,J=6.0 Hz, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 7.21 (d, J=6.0 Hz, 1H), 7.19(s, 1H), 6.88 (d, J=1.6 Hz, 1H), 4.98-4.80 (m, 1H), 3.96 (s, 3H),2.19-2.14 (m, 1H), 1.88-1.78 (m, 1H), 1.27-1.18 (m, 1H).

(±)-trans-N-[8-amino-6-(4-methoxy-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(6 mg, 44%, yellow solid). LCMS (ESI): R_(T) (min)=1.295, [M+H]⁺=353.1,method=A; ¹H NMR (400 MHz,CD₃OD): δ 9.22 (s, 1H), 8.44 (d, J=6.0 Hz,1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.21 (d, J=6.0 Hz, 1H), 7.17 (s, 1H),6.88 (d, J=0.8 Hz, 1H), 4.99-4.78 (m, 1H), 3.96 (s, 3H), 2.50-2.40 (m,1H), 1.55-1.49 (m, 1H), 1.42-1.37 (m, 1H). Example 35(±)-cis-N-[8-amino-6-(2-hydroxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 48)

Step 1:2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a pressure tube was added 3-bromo-2-methoxy-4-methylpyridine (396 mg,1.96 mmol), bis(pinacolato)diboron (597 mg, 2.35 mmol), Pd(dppf)₂Cl₂(143 mg, 0.20 mmol), potassium acetate (384 mg, 3.92 mmol) and1,4-dioxane (15 mL). The mixture was stirred at 95° C. for 4 hours. Theresidue was purified by silica gel flash chromatography (petroleumether/ethyl acetate, 4:1) to give2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(250 mg, 51% yield) as a colourless oil. LCMS (ESI): [M+H]⁺=249.3.

Step 2:(±)-cis-N-[8-chloro-6-(2-methoxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

To a pressure tube was added(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(260 mg, 0.76 mmol),2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(226 mg, 0.91 mmol), Pd(dppf)₂Cl₂ (68 mg, 0.09 mmol), sodium acetate(244 mg, 2.3 mmol), K₃PO₄ (160 mg, 0.76 mmol), acetonitrile (10 mL) andwater (1 mL). The mixture was bubbled through with N₂ for 2 minutes andstirred at 90° C. for 2 hours. The residue was purified by silica gelflash chromatography (petroleum ether/ethyl acetate, 4:1) to afford(±)-cis-N-[8-chloro-6-(2-methoxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(145 mg, 50% yield) as a white solid. LCMS (ESI): [M+H]⁺=386.1.

Step 3:(±)-cis-N-[8-amino-6-(2-methoxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of Pd₂dba₃ (32 mg, 0.03 mmol), Cs₂CO₃ (253 mg, 0.78 mmol),(±)-cis-N-[8-chloro-6-(2-methoxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 0.26 mmol) and tert-butyl carbamate (304 mg, 2.59 mmol), andXantphos (40 mg, 0.07 mmol) in toluene (1 mL) and DMF (1 mL) was heatedat 110° C. for 2 hours. The mixture diluted with ethyl acetate, washedwith water (30 mL), brine (30 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by reverse phase prep-HPLC togive(±)-cis-N-[8-amino-6-(2-methoxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(12 mg, 13% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=367.1.

Step 4:(±)-cis-N-[8-amino-6-(2-hydroxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

To a mixture of(±)-cis-N-[8-amino-6-(2-methoxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(12 mg, 0.03 mmol) in acetonitrile (4 mL) was added iodotrimethylsilane(0.02 mL, 0.14 mmol). The mixture was stirred at 90° C. for 1 hour. Themixture was diluted with ethyl acetate, washed with water (30 mL), brine(30 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by reverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(2-hydroxy-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(9 mg, 78% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.625,[M+H]⁺=353.1, method=I; ¹H NMR (400 MHz, DMSO-d₆) δ 11.26 (s, 1H),10.47(s, 1H), 9.25 (s, 1H), 8.17 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.74(s, 1H), 6.47 (s, 1H), 6.13 (d, J=8.8 Hz, 1H), 5.91 (s, 2H), 5.00-4.76(m, 1H), 2.27-2.23 (m, 1H), 2.00 (s, 3H), 1.74-1.61 (m, 1H), 1.18-1.12(m, 1H).

Example 36(±)-cis-N-[8-amino-6-(5-fluoro-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 49)

Step 1:(±)-cis-N-[8-chloro-6-(5-fluoro-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

To a sealed tube was added(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(200 mg, 0.58 mmol),3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(179 mg, 0.76 mmol), Pd(dppf)₂Cl₂ (52 mg, 0.07 mmol), K₃PO₄ (123 mg,0.58 mmol) and sodium acetate (145 mg, 1.77 mmol), acetonitrile (20 mL)and water (2 mL). The mixture was bubbled through with N₂ for 2 min, andstirred at 90° C. for 3 hours. The mixture was concentrated and purifiedby silica gel flash chromatography (petroleum ether/ethyl acetate, 2:1)to afford(±)-cis-N-[8-chloro-6-(5-fluoro-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 46% yield) as a white solid. LCMS (ESI): [M+H]⁺=374.1.

Step 2:(±)-cis-N-[8-amino-6-(5-fluoro-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of Pd₂dba₃ (33 mg, 0.04 mmol), Cs₂CO₃ (262 mg, 0.80 mmol),(±)-cis-N-[8-chloro-6-(5-fluoro-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 0.27 mmol) and tert-butyl carbamate (313 mg, 2.68 mmol), andXantphos (41 mg, 0.07 mmol) in toluene (1 mL) and DMF (1 mL) was heatedat 110° C. for 2 hours. The mixture was diluted with ethyl acetate,washed with water (30 mL), brine (30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by reverse phase prep-HPLC togive(±)-cis-N-[8-amino-6-(5-fluoro-4-methyl-3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(18 mg, 19% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.422,[M+H]⁺=355.1, method=D; ¹H NMR (400 MHz, CD₃OD) δ 9.25 (s, 1H), 8.39 (d,J=1.2 Hz, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 7.01 (s, 1H), 6.68 (d, J=1.6Hz, 1H), 4.99-4.78 (m, 1H), 2.31 (d, J=2.0 Hz, 3H), 2.18-2.13 (m, 1H),1.87-1.77 (m, 1H), 1.26-1.21 (m, 1H).

Example 37(±)-cis-N-[8-amino-6-(3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 50)

Step 1:(±)-cis-N-[8-chloro-6-(3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

To a sealed tube was addedcis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(300 mg, 0.87 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (214 mg, 1.05mmol), Pd(dppf)₂Cl₂ (78 mg, 0.11 mmol), sodium acetate (281 mg, 2.65mmol), K₃PO₄ (184 mg, 0.87 mmol), acetonitrile (10 mL) and water (1 mL).The mixture was bubbled through with N₂ for 2 minutes, and stirred at90° C. for 2 hours. The mixture was concentrated and purified by silicagel flash chromatography (petroleum ether/ethyl acetate, 1:1) to affordcis-N-[8-chloro-6-(3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(200 mg, 67% yield) as a white solid. LCMS (ESI): [M+H]⁺=342.1.

Step 2:(±)-cis-N-[8-amino-6-(3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of Pd₂dba₃ (66 mg, 0.07 mmol), Cs₂CO₃ (529 mg, 1.62 mmol),cis-N-[8-chloro-6-(3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(185 mg, 0.54 mmol), and tert-butyl carbamate (634 mg, 5.41 mmol),Xantphos (83 mg, 0.14 mmol) in toluene (1 mL) and DMF (1 mL) was heatedat 110° C. for 2 hours. The mixture was diluted with ethyl acetate,washed with water (30 mL), brine (30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by reverse phase prep-HPLC togivecis-N-[8-amino-6-(3-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(20 mg, 11% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.273,[M+H]⁺=323.0, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 8.89 (d,J=1.6 Hz, 1H), 8.56 (dd, J=1.6, 4.8 Hz, 1H), 8.37 (s, 1H), 8.21-8.18 (m,1H), 7.56 (dd, J=4.8, 8.0 Hz, 1H), 7.34 (s, 1H), 7.01(d, J=1.2 Hz, 1H),4.99-4.79 (m, 1H), 2.20-2.13 (m, 1H), 1.88-1.78 (m, 1H), 1.27-1.19(m,1H).

Example 38(±)-trans-N-[8-amino-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 51)

Step 1:(±)-trans-N-[8-chloro-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a sealed tube was added(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(150 mg, 0.43 mmol), 3-methylpyridine-4-boronicacid (70 mg, 0.51 mmol),Pd(dppf)₂Cl₂ (39 mg, 0.05 mmol) and Na₂CO₃ (138 mg, 1.3 mmol),1,4-dioxane (10 mL) and water (1 mL). The mixture was bubbled throughwith N₂ for 2 min, and then heated in microwave reactor at 120° C. for 1hour. The mixture was concentrated and purified by prep-TLC (ethylacetate/petroleum ether, 1:1) to affordtrans-N-[8-chloro-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(70 mg, 45% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=363.1.

Step 2:(±)-trans-N-[8-amino-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a sealed tube was added(±)-trans-N-[8-chloro-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(60 mg, 0.17 mmol), tert-butyl carbamate (157 mg, 1.35 mmol), Pd₂(dba)₃(31 mg, 0.03 mmol), NaOtBu (47 mg, 0.49 mmol), tBuBrettPhos (19 mg, 0.04mmol) and 1-methyl-2-pyrrolidinone (5 mL). The mixture was stirred at110° C. for 2 hours. The mixture was diluted with ethyl acetate, washedwith water (30 mL), brine (30 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by prep-TLC (ethyl acetate)and reverse phase prep-HPLC to give(±)-trans-N-[8-amino-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(3 mg, 5% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.338,[M+H]⁺=344.2, method=D; ¹H NMR (400 MHz, CD₃OD) δ 9.26 (s, 1H), 8.47 (s,1H), 8.41(d, J=5.2 Hz, 1H), 8.30 (s, 1H), 7.35 (d, J=5.2 Hz, 1H), 7.00(s, 1H), 6.69 (d, J=1.2 Hz, 1H), 2.64-2.63(m, 1H), 2.34 (s, 3H),2.12-2.10(m, 1H), 1.60-1.53(m, 2H).

Example 39(±)-trans-N-[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 52)

Step 1:(±)-trans-N-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide

To a solution of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (800 mg,2.48 mmol) in dichloromethane (10 mL) and pyridine (0.6 mL, 7.44 mmol)was added (±)-trans-2-cyanocyclopropanecarbonyl chloride (830 mg, 6.41mmol). The mixture was stirred at 25° C. for 2 hours. The mixture wasconcentrated and re-suspended in water (10 mL). The mixture wasextracted with ethyl acetate (50 mL×3). The organic layer was washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated. Thecrude product was suspended in 100 ml of petroleum ether and 10 ml ofethyl acetate and then filtered to give(±)-trans-N-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(800 mg, 78% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=416.0.

Step 2:(±)-trans-N-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a sealed tube was added(±)-trans-N-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(400 mg, 0.96 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (253mg, 1.15 mmol), Pd(dppf)₂Cl₂ (84 mg, 0.12 mmol) and Na₂CO₃ (255 mg, 2.41mmol), tetrahydrofuran (20 mL) and water (8 mL). The mixture was bubbledthrough with N₂ for 2 minutes, and stirred at 65° C. for 3 hours. Water(50 mL) was then added. The mixture was extracted with ethyl acetate (50mL×3). The combined organic extracts were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby silica gel flash chromatography (petroleum ether/ethyl acetate, 1:1)to afford(±)-trans-N-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(220 mg, 60% yield) as a white solid. LCMS (ESI): [M+H]⁺=381.1.

Step 3:(±)-trans-N-[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of Pd₂dba₃ (96 mg, 0.11 mmol), Cs₂CO₃ (513 mg, 1.58 mmol),trans-N-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 0.53 mmol), tert-butyl carbamate (615 mg, 5.25 mmol), andXantphos (121 mg, 0.21 mmol) in toluene (6 mL) and DMF (6 mL) was heatedovernight at 130° C. The mixture was diluted with ethyl acetate, washedwith water (30 mL), brine (30 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by reverse phase prep-HPLC togive(±)-trans-N-[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(20 mg, 10.5% yield). LCMS (ESI): R_(T) (min)=1.330, [M+H]⁺=362.1,method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.32 (s, 1H), 8.47 (d, J=5.2 Hz,1H), 8.41(s, 1H), 8.33 (s, 1H), 7.42 (d, J=5.2 Hz, 1H), 6.99 (d, J=6.4Hz, 1H), 2.65-2.61 (m, 1H), 2.30 (s, 3H), 2.14-2.09 (m, 1H), 1.61-1.52(m, 2H).

Example 40(±)-trans-N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 54)

Step 1:(±)-trans-N-(8-chloro-6-(3-(4-methoxybenzyl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(90 mg, 0.26 mmol), Pd(dppf)Cl₂ (18 mg, 0.03 mmol), K₂CO₃ (70 mg, 0.51mmol),3-[(4-methoxyphenyl)methyl]-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one(101 mg, 0.26 mmol), water (0.2 mL) and 1,4-dioxane (10 mL) was stirredat 100° C. under N₂ for 4 hours. The mixture was concentrated andpurified by silica gel column chromatography (30% ethyl acetate inpetroleum ether) to give(±)-trans-N-[8-chloro-6-[3-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-1,3-benzoxazol-6-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(90 mg, 62% yield) as a white solid. LCMS (ESI): [M+H]⁺=539.2

Step 2: (±)-tert-butyl3-(trans-2-cyanocyclopropanecarboxamido)-6-(3-(4-methoxybenzyl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-8-ylcarbamate

To a sealed tube was addedtrans-N-[8-chloro-6-[3-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-1,3-benzoxazol-6-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(75 mg, 0.14 mmol), Pd₂(dba)₃ (25 mg, 0.03 mmol), t-BuONa (27 mg, 0.28mmol), tert-butyl carbamate (326 mg, 2.78 mmol) and 1,4-dioxane (4 mL).The mixture was stirred at 90° C. for 1 hour. The mixture wasconcentrated and the residue was purified by silica gel columnchromatography (0-50% ethyl acetate in petroleum ether) to give(±)-tert-butylN-[3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-[3-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-1,3-benzoxazol-6-yl]-8-isoquinolyl]carbamate(60 mg, 70% yield) as a brown solid. LCMS (ESI): [M+H]⁺=620.3.

Step 3:(±)-trans-N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of (±)-tert-butylN-[3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-[3-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-1,3-benzoxazol-6-yl]-8-isoquinolyl]carbamate(20 mg), TFA (0.5 mL), and trifluoromethanesulfonic acid (1 mL) wasstirred at 25° C. for 2 hours. The mixture was concentrated and basifiedwith NH₃ in methanol (7M). The resulting residue was purified by reversephase prep-HPLC (acetonitrile 0-50/0.1% formic acid in water) to afford(±)-trans-N-[8-amino-6-(5-methyl-2-oxo-3H-1,3-benzoxazol-6-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(4 mg, 31% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.669,[M+H]⁺=400.1, method=B; ¹H NMR (400 MHz, DMSO-d₆) δ 11.14(s, 1H), 9.36(s, 1H), 8.26 (s, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.61(s,1H), 6.35 (s, 2H), 2.83-2.78 (m, 1H), 2.30 (s, 3H), 2.21-2.16 (m, 1H),1.66-1.62 (m, 1H), 1.51-1.46 (m, 1H).

Example 41(±)-cis-N-(8-amino-6-(2-ethyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 55)

Step 1:(±)-cis-N-(8-chloro-6-(2-ethyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(150 mg, 0.5 mmol) , 5-ethylpyrrolidin-2-one (56 mg, 0.5 mmol),Pd₂(dba)₃ (45 mg, 0.05 mmol) , Cs₂CO₃ (324 mg, 1.0 mmol), Xantphos (58mg, 0.1 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. under N₂ for16 hours. The mixture was concentrated and the residue was purified bysilica gel column chromatography (0-100% ethyl acetate in petroleumether) to give(±)-cis-N-[8-chloro-6-[2-ethyl-5-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(120 mg, 64% yield) as a white solid. LCMS (ESI): [M+H]⁺=376.1.

Step 2:(±)-cis-N-(8-amino-6-(2-ethyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-(2-ethyl-5-oxo-pyrrolidin-1-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(100 mg, 0.27 mmol), tert-butyl carbamate (311 mg, 2.66 mmol),tert-BuBrettphos (51 mg, 0.108 mmol), Pd₂(dba)₃ (47 mg, 0.054 mmol), andt-BuONa (51 mg, 0.53 mmol) in 1-methyl-2-pyrrolidinone (1 mL) wasstirred at 110° C. under N₂ for 2 hours. The mixture was concentratedand purified by silica gel column chromatography (0-100% ethyl acetatein petroleum ether) to give(±)-cis-N-[8-amino-6-(2-ethyl-5-oxo-pyrrolidin-1-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(6 mg , 6.3% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.625,[M+H]⁺=356.7, method=C; ¹H NMR (400 MHz, CD3OD) δ 9.15 (s, 1H), 8.26 (s,1H), 7.07-7.04 (m, 1H), 6.85-6.84 (m, 1H), 5.00-4.78 (m, 1H), 4.43-4.35(m, 1H), 2.67-2.54 (m, 2H), 2.43-2.34 (m , 1H), 2.20-2.10 (m, 1H),1.97-1.69 (m,3H), 1.55-1.47 (m, 1H), 1.26-1.17 (m, 1H), 0.91 (t, J=7.2Hz, 3H).

Example 42(±)-trans-N-(8-amino-6-(6-ethoxy-4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 56)

Step 1:(±)-trans-N-(8-amino-6-(4-ethylpyridin-3-yl)-2,7-naphthyridin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(6-ethoxy-4-ethyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.24 mmol), tert-butyl carbamate (555 mg, 4.74 mmol),t-BuBrettphos (46 mg, 0.1 mmol), Pd₂(dba)₃ (43 mg, 0.05 mmol), andt-BuONa (45 mg, 0.48 mmol) in 1-methyl-2-pyrrolidinone (4 mL) wasstirred at 110° C. for 2 hours. The mixture was concentrated andpurified by silica gel column chromatography (0-100% ethyl acetate inpetroleum ether) to give(±)-trans-N-[8-amino-6-(6-ethoxy-4-ethyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(6 mg, 6.3% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.956,[M+H]⁺=402.2, method=C; ¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 8.26 (s,1H), 7.94 (s, 1H), 6.95 (s, 1H), 6.76 (s, 1H), 6.67 (d, J=1.6 Hz, 1H),4.35(q, J=6.8 Hz, 2H), 2.69-2.63 (m, 3H), 2.14-2.09 (m, 1H) , 1.61-1.53(m, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.12 (t, J=7.6 Hz, 3H).

Example 43(±)-trans-N-(8-amino-6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 57)

Step 1:1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole

In a glove box, a pressure tube was charged with [Ir(OMe)(COD)]₂ (105mg, 0.16 mmol), THF (5 mL), and pinacolborane (1.1 mL, 7.8 mmol). Thereaction mixture was stirred at room temperature for 10 minutes and tothis 4,4-di-tert-butyl bipyridine (42 mg, 0.16 mmol) was added. Thereaction was stirred at room temperature for an additional 10 minutes. Asolution of 1,2-dimethylimidazole (500 mg, 5.2 mmol) in THF (5 mL) wasadded. The mixture was stirred at room temperature for 16 hours. Themixture was then concentrated in vacuo. The residue was washed withhexane (10 mL×4) and concentrated to give1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole(1g, 52% yield) as a brown solid. LCMS (ESI) [M+H]⁺=223.2.

Step 2:(±)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-methylcyclopropanecarboxamide

To a sealed tube was added(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(220 mg, 0.63 mmol),1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole(385 mg, 1.73 mmol), Pd(dppf)Cl₂ (101 mg, 0.14 mmol) and Na₂CO₃ (202 mg,1.91 mmol), 1,4-dioxane (10 mL) and water (1 mL). The mixture wasbubbled through with N₂ for 2 minutes and stirred at 100° C. for 2.5hours. The mixture was concentrated and purified by silica gel flashchromatography (petroleum ether/ethyl acetate, 1:1 to 0:100) to give(±)-trans-N-[8-chloro-6-(2,3-dimethylimidazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(250 mg, 97% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=366.1.

Step 3:(±)-trans-N-(8-amino-6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (768 mg, 6.56 mmol),(±)-trans-N-[8-chloro-6-(2,3-dimethylimidazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(240 mg, 0.66 mmol), Pd₂(dba)₃ (150 mg, 0.16 mmol), Cs₂CO₃ (700 mg, 2.15mmol), Xantphos (100 mg, 17 mmol) and 1-methyl-2-pyrrolidinone (15 mL).The mixture was stirred at 130° C. for 2 hours. The reaction mixture wasconcentrated in vacuum and purified by column chromatography (BOSTOM ODS40 g column, eluted with 10 mM NH₄HCO₃ in acetonitrile from 100:0 to1:5) to give the crude product (100 mg). The crude product was purifiedagain by prep-TLC (silica-gel, dichloromethane/methanol, 10:1) to give(±)-trans-N-[8-amino-6-(2,3-dimethylimidazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(10 mg, 4% yield) as a pale-yellow solid. LCMS (ESI): R_(T) (min)=1.532,[M+H]⁺=346.8, method=H; ¹H NMR (400 MHz, CD₃OD) δ: 9.19 (s, 1H), 8.27(s, 1H), 7.06 (s, 1H), 6.98 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 3.66 (s,3H), 2.67-2.60 (m, 1H), 2.45 (s, 3H), 2.13-2.04 (m, 1H), 1.63-1.50 (m,2H).

Example 44(±)-cis-N-[8-amino-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(Compound 59)

Step 1:(±)-cis-N-(8-chloro-6-(3-methylpyridin-4-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

To a sealed tube was added(±)-cis-N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(200 mg, 0.58 mmol), 3-methylpyridine-4-boronic acid (95 mg, 0.70 mmol),Pd(dppf)Cl₂ (52 mg, 0.07 mmol), K₃PO₄ (122 mg, 0.58 mmol), sodiumacetate (185 mg, 1.75 mmol), acetonitrile (20 mL) and water (2 mL). Themixture was stirred at 90° C. for 3 hours under N₂. The mixture wasconcentrated and purified by silica gel flash chromatography (petroleumether/ethyl acetate, 2:3) to afford(±)-cis-N-[8-chloro-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(140 mg, 67% yield) as a white solid. LCMS (ESI): [M+H]⁺=356.1.

Step 2:(±)-cis-N-[8-amino-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide

A mixture of(±)-cis-N-[8-chloro-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(130 mg, 0.37 mmol), tert-butyl carbamate (428 mg, 3.65 mmol), Pd₂dba₃(66 mg, 0.07 mmol), Xantphos (84 mg, 0.15 mmol), and Cs₂CO₃ (357 mg, 1.1mmol) in toluene (3 mL) and DMF (3 mL) was heated in a sealed tube at110° C. for 16 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was washed with petroleumether and ethyl acetate to give the crude product, which was purified byreverse phase prep-HPLC to give(±)-cis-N-[8-amino-6-(3-methyl-4-pyridyl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(25 mg, 20% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.605,[M+H]⁺=337.1, method=C; ¹H NMR (400 MHz, CD₃OD) δ 9.25 (s, 1H), 8.48 (s,1H), 8.43 (d, J=4.8 Hz , 1H), 8.33 (s, 1H), 7.36 (d, J=4.8 Hz , 1H),7.02 (s, 1H), 6.69 (d, J=1.2 Hz , 1H), 4.99-4.79 (m, 1H), 2.35 (s, 3H),2.20-2.12 (m, 1H), 1.87-1.77 (m, 1H), 1.27-1.18 (m, 1H).

Example 45(±)-((trans)-N-(8-amino-6-(4-(1,1-difluoroethyl)pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 60)

Step 1:4-(1,1-difluoroethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 3-bromo-4-(1,1-difluoroethyl)pyridine (500 mg, 2.25 mmol),bis(pinacolato)diboron (857 mg, 3.37 mmol), PdCl₂dppf (164 mg, 0.22mmol), and potassium acetate (662 mg, 6.76 mmol) in 1,4-dioxane (10 mL)was heated at 100° C. for 16 hours under Ar. The reaction wasconcentrated to dryness. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=10:1 to petroleumether/ethyl acetate=2:1) to give the title compound as a yellow oil (105mg, 17% yield). LCMS (ESI) [M+H]⁺=270.2.

Step 2:(±)-(trans)-N-(8-chloro-6-(4-(1,1-difluoroethyl)pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(108 mg, 0.31 mmol),4-(1,1-difluoroethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(100 mg, 0.37 mmol), Pd(PPh₃)₄ (36 mg, 0.03 mmol), potassium acetate (90mg, 0.92 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 90°C. for 4 hours under Ar. The reaction was concentrated to dryness. Theresidue was purified by silica gel column chromatography (petroleumether/ethyl acetate=4:1 to petroleum ether/ethyl acetate=2:1) to givethe title compound as a white solid (80 mg, 61% yield). LCMS (ESI)[M+H]⁺=413.1.

Step 3:(±)-trans-2-cyano-N-(6-(4-(1,1-difluoroethyl)pyridin-3-yl)-8-(diphenylmethyleneamino)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-[4-(1,1-difluoroethyl)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(70 mg, 0.17 mmol), benzophenone imine (92 mg, 0.51 mmol), Pd₂(dba)₃ (31mg, 0.03 mmol), Xantphos (10 mg, 0.02 mmol), Cs₂CO₃ (165 mg, 0.51 mmol)in DMF (0.5 mL) and toluene (0.5 mL) was heated at 130° C. for 3 hoursunder Ar. The reaction was diluted with ethyl acetate and washed withbrine. The organic layer was separated, dried (NaSO₄) and concentratedto dryness. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=4:1 to petroleum ether/ethyl acetate=2:1)to give the title compound as a yellow solid (25 mg, 23.6% yield). LCMS(ESI) [M+H]⁺=558.2.

Step 4:(±)-trans-N-(8-amino-6-(4-(1,1-difluoroethyl)pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-(trans)-N-[8-(benzhydrylideneamino)-6-[4-(1,1-difluoroethyl)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(25 mg, 0.04 mmol) and TFA (0.5 mL, 6.71 mmol) in dichloromethane (2 mL)and two drops of water was stirred at room temperature for 2 hours underN₂. The reaction was concentrated to dryness. The residue was taken upin methanol (0.5 mL) and adjusted pH to 7-8 with sat NaHCO₃. The mixturewas purified directly by reverse phase prep-HPLC (eluent: 5%-95%methanol and water) to give the title compound as a yellow solid (14.2mg, 81% yield). LCMS (ESI): R_(T)(min)=1.75, [M+H]⁺=394.2, method=B. ¹HNMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 9.35 (s, 1H), 8.75 (d, J=5.2 Hz,1H), 8.51 (s, 1H), 8.21 (s, 1H), 7.64 (d, J=5.6Hz, 1H), 6.87 (s, 1H),6.53 (s, 1H), 6.41 (s, 2H), 2.77-2.50 (m, 1H), 2.14-2.10 (m, 1H), 1.77(t, J=19.2 Hz, 1H), 1.61-1.58 (m, 1H), 1.44-1.43 (m, 1H).

Example 46(±)-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(morpholin-3-yl)acetamide(Compound 61)

Step 1: 8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (2000 mg, 7.77 mmol) ,4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2042mg, 9.32 mmol) , Pd(dppf)Cl₂ (284 mg, 0.39 mmol), and Na₂CO₃ (2058 mg,19.42 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 90°C. for 2 hours. The reaction was concentrated. The residue was purifiedby silica gel flash column chromatography (petroleum ether/ethylacetate, 2:1 to 1:4) to give8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (1.3 g, 52% yield) asa yellow solid. LCMS (ESI): [M+H]⁺=270.1.

Step 2: (±)-tert-butyl3-(2-(8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-2-oxoethyl)morpholine-4-carboxylate

To a solution of 8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (130mg, 0.48 mmol) and 2-(4-tert-butoxycarbonylmorpholin-3-yl)acetic acid(142 mg, 0.58 mmol) in pyridine (2 mL) was added phosphorus oxychloride(369 mg, 2.4 mmol). The resulting mixture was stirred at 25° C. for 1hour. The mixture was concentrated and purified by silica gel flashcolumn chromatography (petroleum ether/ethyl acetate, 3:1 to 1:2) togive (±)-tert-butyl3-[2-[[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-2-oxo-ethyl]morpholine-4-carboxylate(130 mg, 48% yield) as a yellow solid. LCMS (ESI): [M+I-I]⁺=497.2.

Step 3: (±)-tert-butyl3-(2-(8-(tert-butoxycarbonylamino)-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-2-oxoethyl)morpholine-4-carboxylate

A mixture of (±)-tert-butyl carbamate (259 mg, 2.21 mmol),tert-butoxysodium (234 mg, 2.43 mmol), tert-butyl3-[2-[[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-2-oxo-ethyl]morpholine-4-carboxylate(110 mg, 0.22 mmol) , Pd₂(dba)₃ (20 mg, 0.02 mmol) and Brettphos (24 mg,0.04 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 1 hour. Thereaction was concentrated and purified by silica gel flash columnchromatography (petroleum ether:ethyl acetate, 3:1 to 1:3) to give(±)-tert-butyl3-[2-[[8-(tert-butoxycarbonylamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-2-oxo-ethyl]morpholine-4-carboxylate(36 mg, 23% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=578.3.

Step 4:(±)-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(morpholin-3-yl)acetamide

A mixture of (±)-tert-butyl3-[2-[[8-(tert-butoxycarbonylamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-2-oxo-ethyl]morpholine-4-carboxylate(36 mg, 0.06 mmol) in 0.5 mL of 4 M HCl in 1,4-dioxane was stirred for 1hour. The reaction was concentrated and purified by reverse phase HPLC(acetonitrile 10-47/0.05% ammonia in water) to give(±)-N-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-morpholin-3-yl-acetamide(7.1 mg, 30.2% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.490,[M+H]⁺=378.2, method=C; ¹H NMR (400 MHz, DMSO-d₆): 10.62 (s, 1H), 9.30(s, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.35 (d,J=4.8 Hz, 1H), 6.92 (s, 1H), 6.56 (s, 1H), 6.33(s, 2H), 3.71-3.63 (m,2H), 3.22-3.20 (m, 1H), 3.12-3.10 (m, 2H), 2.78-2.75 (m, 2H), 2.41-2.40(m, 2H), 2.30 (s, 3H).

Example 47(±)-trans-N-(8-amino-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 62)

Step 1:(±)-trans-N-(8-chloro-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-8-chloro-3-(2-cyanocyclopropanecarboxamido)isoquinolin-6-ylboronicacid (240 mg, 0.76 mmol), 5-bromo-4-methyl-isothiazole (162 mg, 0.91mmol), Pd(dppf)Cl₂ (28 mg, 0.04 mmol), and Na₂CO₃ (161 mg, 1.52 mmol) in1,4-dioxane (4 mL) and water (0.4 mL) was stirred at 90° C. for 3 hours.The mixture was concentrated. The residue was purified by silica gelflash column chromatography (petroleum ether/ethyl acetate, 5:1 to 1:5)to give(±)-trans-N-[8-chloro-6-(4-methylisothiazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(190 mg, 48% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=369.0.

Step 2:(±)-trans-2-cyano-N-(8-(diphenylmethyleneamino)-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(4-methylisothiazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(90 mg, 0.24 mmol), benzophenone imine (88 mg, 0.49 mmol), Pd₂(dba)₃ (45mg, 0.05 mmol), Xantphos (56 mg, 0.10 mmol), and Cs₂CO₃ (161 mg, 0.49mmol) in DMF (2 mL) and toluene (2 mL) was stirred at 130° C. for 3hours. The reaction was then cooled to room temperature and diluted withwater (10 mL). The mixture was extracted with ethyl acetate (20 mL×2).The combined organic extracts were concentrated in vacuo. The residuewas purified by silica gel column chromatography (petroleum ether/ethylacetate, 3:1 to 1:2) to give(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-methylisothiazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(36 mg, 20% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=514.2.

Step 3:(±)-trans-N-(8-amino-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-methylisothiazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(36 mg, 0.05 mmol) in acetonitrile (3 mL) was added 1 drop of TFA and 1drop of water . The resulting solution was stirred for 20 minutes. Thereaction solution was concentrated and purified by reverse phaseprep-HPLC (acetonitrile 10-47/0.05% ammonia in water) to give(±)-trans-N-[8-amino-6-(4-methylisothiazol-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(8 mg, 47% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.759,[M+H]⁺=350.1, method=C; ¹H NMR (400 MHz, DMSO-d₆): 9.34 (s, 1H), 8.47(s, 1H), 8.28 (s, 1H), 7.09 (s, 1H), 6.74 (d, J=1.6 Hz, 1H), 6.52 (s,2H), 6.08 (d, J=1.6 Hz, 1H), 2.78-2.74 (m, 1H), 2.40 (s, 3H), 2.17-2.12(m, 1H), 1.62-1.60 (m, 1H), 1.46-1.42 (m, 1H).

Example 48(±)-trans-N-[8-amino-6-[6-(difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 63)

Step 1: 5-bromo-2-(difluoromethoxy)-4-ethyl-pyridine

A mixture of 5-bromo-4-ethyl-pyridin-2-ol (1.0 g, 4.9 mmol), cesiumcarbonate (2.4 g, 7.4 mmol) and sodium chlorodifluoroacetate (760 mg,5.0 mmol) in DMF (20 mL) was stirred at 100° C. for 3 hours. The cooledmixture was diluted with water (30 mL) and extracted with ether (25 mL).The organic phase was washed with water then brine, dried (Na₂SO₄), andconcentrated. The major isomer, the O-alkylated product, was isolated bysilica gel flash chromatography (0-10% ethyl acetate in hexane) to givethe title compound (130 mg, 8.5% yield) as a colorless liquid. LCMS(ESI): [M+H]⁺=253.1.

Step 2:2-(difluoromethoxy)-4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Bis(pinacolato)diborane (220 mg, 0.9 mmol), potassium acetate (100.0 mg,1.0 mmol) and Pd(dppf)Cl₂ (40 mg, 0.05 mmol) were added sequentially toa solution of 5-bromo-2-(difluoromethoxy)-4-ethyl-pyridine (110 mg, 0.4mmol) in 1,4-dioxane (10 mL) under an Ar atmosphere. The reactionmixture was stirred overnight at 100° C. The reaction mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether, 0-100% yield) to afford2-(difluoromethoxy)-4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(150 mg, 63% yield) as a light yellow oil. LCMS (ESI): [M+H]⁺=300.1.

Step 3:(±)-trans-N-[8-chloro-6-[6-(difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(100 mg, 0.3 mmol), Pd(PPh₃)₄ (35 mg, 0.03 mmol) and K₃PO₄ (120 mg, 0.6mmol) were added sequentially to a solution of2-(difluoromethoxy)-4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(105 mg, 0.4 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL). Thereaction mixture was stirred at 100° C. for 2 hours. The reactionmixture was concentrated in vacuo. The residue was purified on silicagel column chromatography (methanol/dichloromethane, 1:3) to afford(±)-trans-N-[8-chloro-6-[6-(difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 53% yield) as a white solid. LCMS (ESI): [M+H]⁺=443.1.

Step 4:(±)-trans-N-[8-amino-6-[6-(difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of tert-butyl carbamate (265.0 mg, 2.3 mmol),(±)-trans-N-[8-chloro-6-[6-(difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.23 mmol), Pd₂(dba)₃ (40 mg, 0.04 mmol), NaOtBu (55.0 mg, 0.6mmol) and tBu-Brettphos (49.0 mg, 0.09 mmol) in dichloromethane (5 mL)was stirred at 120° C. for 1 h under N₂. The reaction mixture wasconcentrated in vacuum and the residue was purified by silica gel flashchromatography (ethyl acetate/petroleum ether, 0 to 50% yield) andreverse phase prep-HPLC to give(±)-trans-N-[8-amino-6-[6-(difluoromethoxy)-4-ethyl-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(3 mg, 3.1% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.950,[M+H]⁺=424.2, method=F; ¹H NMR (400 MHz, CD₃OD) δ: 9.26 (s, 1H), 8.28(s, 1H), 8.06 (s, 1H), 7.58 (t, J=73.2 Hz, 1H), 6.97 (s, 2H), 6.67 (s,1H), 2.71 (q, J=7.6 Hz, 2H), 2.68-2.65 (m, 1H), 2.14-2.09 (m, 1H),1.63-1.52 (m, 2H), 1.15 (t, J=7.6 Hz, 3H).

Example 49(±)-trans-N-[8-amino-6-[4-(2-hydroxyethyl)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 65)

Step 1: methyl 2-(3-bromo-4-pyridyl)acetate

To an ice-cooled solution of 3-bromo-4-methylpyridine (1.0 g, 5.8 mmol)and dimethyl carbonate (950.0 mg, 10.6 mmol) in tetrahydrofuran (10 mL)was added LiHMDS (1.0 M in THF, 9 mL, 9 mmol). After stirring at 0° C.for 5 hours, additional LiHMDS (1.0 M in THF, 6 mL, 6 mmol) was added.The mixture was stirred at room temperature for 2 hours. The reactionmixture was quenched by the addition of a saturated aqueous NH₄Clsolution and extracted with ethyl acetate. The organic layer was dried,filtered and concentrated. The crude product was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate=1:3) to give methyl2-(3-bromo-4-pyridyl)acetate (1.2 g, 85% yield) as a colorless oil. LCMS(ESI): [M+H]⁺=231.1.

Step 2: 2-(3-bromo-4-pyridyl)ethanol

To an ice-cooled solution of methyl 2-(3-bromo-4-pyridyl)acetate (800mg, 3.5 mmol) in methyl alcohol (10 mL) was added NaBH₄ (264.0 mg, 6.9mmol) in portions. The mixture was stirred at room temperature for 2hours. The mixture was concentrated and purified by silica gel columnchromatography (petroleum ether/ethyl acetate, 1:1) to give2-(3-bromo-4-pyridyl)ethanol (550 mg, 78% yield) as a colorless oil.LCMS (ESI): [M+H]⁺=203.1.

Step 3: 243-(3-amino-8-chloro-6-isoquinolyl)-4-pyridyflethanol

2-(3-bromo-4-pyridyl)ethanol (300 mg, 1.5 mmol), Pd(dppf)Cl₂ (120 mg,0.16 mmol), sodium acetate (300 mg, 3.7 mmol), and K₃PO₄ (600 mg, 2.8mmol) were added sequentially to a solution8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine(800 mg, 2.6 mmol) in acetonitrile (15 mL) and water (2 mL). Thereaction mixture was stirred at 90° C. for 4 hours. The reaction wasconcentrated to dryness. The residue was purified by silica gel flashcolumn chromatography (30% methanol in dichloromethane) to give2-[3-(3-amino-8-chloro-6-isoquinolyl)-4-pyridyl]ethanol (400 mg, 84%yield) as a yellow solid. LCMS (ESI): [M+H]⁺=300.1.

Step 4:6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-8-chloro-isoquinolin-3-amine

A mixture of 2-[3-(3-amino-8-chloro-6-isoquinolyl)-4-pyridyl] ethanol(400.0 mg, 1.3 mmol), tert-butyldimethylchlorosilane (2.0 g, 13.3 mmol)and triethylamine (3.0 g, 29.7 mmol) in dichloromethane (50 mL) wasrefluxed overnight. The reaction mixture was concentrated The residuewas purified with silica-gel column chromatography (petroleumether/ethyl acetate, 2:1 to 1:1) to give6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-8-chloro-isoquinolin-3-amine(350 mg, 62% yield) as a light brown solid. LCMS (ESI): [M+H]⁺=415.2.

Step 5:(±)-trans-N-[6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-8-chloro-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

Oxalyl chloride (350 mg, 2.8 mmol) was added dropwise to a suspension oftrans-2-cyanocyclopropane carboxylic acid (200 mg, 1.8 mmol) indichloromethane (1 mL) at 0° C. and the mixture was stirred at 0° C. for1 hour. The mixture was concentrated at room temperature to removedichloromethane and the excess oxalyl chloride. The residue wassuspended in dichloromethane (1 mL) and was added dropwise to a mixtureof6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-8-chloro-isoquinolin-3-amine(360 mg, 0.87 mmol), pyridine (5.1 mL, 63.2 mmol) in dichloromethane (2mL) at 0° C. The reaction mixture was stirred at 0° C. for an additional0.5 hours. The reaction mixture was diluted with dichloromethane (100mL) and washed with H₂O (50 mL). The organic layer was separated, driedover Na₂SO₄, filtered and evaporated. The residue was purified by silicagel column chromatography (petroleum ether/ethyl acetate, 1:1 to 1:2) togive(±)-trans-N-[6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-8-chloro-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(350 mg , 63% yield) as a light brown solid. LCMS (ESI): [M+H]⁺=508.1.

Step 6: (±)-tert-butylN-[6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-8-isoquinolyl]carbamate

A mixture of(±)-trans-N-[6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-8-chloro-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(330 mg, 0.65 mmol), tert-butyl carbamate (1.5 g, 12.8 mmol), Pd₂(dba)₃(120 mg, 0.1300 mmol), Brettphos (130 mg, 0.24 mmol), and t-BuONa (170mg, 1.7 mmol) in 1,4-dioxane (10 mL) was stirred at 90° C. under N₂ for1 hour. The reaction mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether, 1:1) to afford (±)-tert-butylN-[6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-8-isoquinolyl]carbamate(220 mg, 52% yield) as a light yellow oil. LCMS (ESI): [M+H]⁺=588.1.

Step 7:(±)-trans-N-[8-amino-6-[4-(2-hydroxyethyl)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of (±)-tert-butylN-[6-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-pyridyl]-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-8-isoquinolyl]carbamate(200 mg, 0.34 mmol) and TFA (10 mL, 134.6 mmol) in dichloromethane (10mL) was stirred at room temperature for 2 hours. The reaction wasconcentrated and purified by reverse phase prep-HPLC to give(±)-trans-N-[8-amino-6-[4-(2-hydroxyethyl)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (82 mg, 65% yield) as a yellow solid. LCMS (ESI): RT(min)=1.409, [M+H]⁺=374.2, method=G; 1H NMR (400 MHz, CD₃OD) δ 9.26 (s,1H), 8.47 (d, J=5.2 Hz, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.49 (d, J=5.2Hz, 1H), 7.01 (s, 1H), 6.70 (d, J=1.2 Hz, 1H), 3.70 (t, J=6.8 Hz, 2H),2.94 (t, J=6.8 Hz, 2H), 2.70-2.61 (m, 1H), 2.17-2.06 (m, 1H), 1.66-1.49(m, 2H).

Example 50(1S,2S)—N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(Compound 66)

Step 1:(1S,2S)—N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide

A mixture of(1S,2S)—N-(6-bromo-8-chloroisoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(130 mg, 0.381 mmol), bis(pinacolato)diboron (148 mg, 0.572 mmol),potassium acetate (112 mg, 1.14 mmol) and Pd(dppf)Cl₂ (28.2 mg, 0.038mmol) in 1,4-dioxane (3 mL) was heated in a microwave at 130° C. for 20minutes to give(8-chloro-3-((1S,2S)-2-fluorocyclopropane-1-carboxamido)isoquinolin-6-yl)boronicacid. LCMS (ESI): [M+H]⁺=309.0.

3-Bromo-4-ethylpyridine (106 mg, 0.574 mmol) and water (0.5 ml, 30 mmol)were added to the reaction mixture. The reaction was heated in amicrowave at 140° C. for 2 hours. The organic layer was purified withsilica-gel column chromatography (0 to 7% methanol in dichloromethane)to give(1S,2S)—N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(120 mg, 84.8% yield). LCMS (ESI) [M+H]⁺=370.0.

Step 2: tert-butyl(6-(4-ethylpyridin-3-yl)-3-((1S,2S)-2-fluorocyclopropane-1-carboxamido)isoquinolin-8-yl)carbamate

A mixture of(1S,2S)—N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(120 mg, 0.325 mmol), tert-butyl carbamate (194 mg, 1.622 mmol),Pd₂(dba)₃ (15 mg, 0.016 mmol), Brettphos (9.168 mg, 0.016 mmol), andtBuONa (47 mg, 0.0.487 mmol) in 1,4-dioxane (5 mL) was stirred under Arat 70° C. for 5 hours. The reaction was concentrated to dryness. Theresidue was purified by silica gel column chromatography (0 to 8%methanol in dichloromethane) to give the title compound (74 mg, 50.6%yield). LCMS (ESI) [M+H]⁺=451.0.

Step 3:(1S,2S)—N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide

A mixture oftert-butyl-(6-(4-ethylpyridin-3-yl)-3-((1S,2S)-2-fluorocyclopropane-1-carboxamido)isoquinolin-8-yl)carbamate(74 mg, 0.164 mmol) in dichloromethane (4 mL) and 2,2,2-trifluoroaceticacid (0.5 mL) was stirred at 25° C. for 2 hours. The mixture wasconcentrated and purified by reverse phase prep-HPLC to afford(1S,2S)—N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(9.3 mg, 15.8% yield) as a solid. LCMS (ESI) R_(T) (min)=2.808,[M+H]⁺=351.1, method=T. ¹H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 9.32 (s,1H), 8.49 (d, J=5.1 Hz, 1H), 8.39-8.35 (m, 1H), 8.27 (s, 1H), 7.38 (d,J=5.2 Hz, 1H), 6.88 (s, 1H), 6.53 (d, J=1.5 Hz, 1H), 6.34 (s, 2H),5.04-4.81 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 2.26 (dq, J=14.1, 7.1 Hz,1H), 1.73-1.59 (m, 1H), 1.17 (ddt, J=13.1, 9.8, 6.7 Hz, 1H), 1.13-1.06(m, 3H).

Example 51(±)-trans-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 67)

Step 1:(±)-trans-N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloroisoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(150 mg, 0.428 mmol), bis(pinacolato)diboron (166 mg, 0.642 mmol),potassium acetate (126 mg, 1.28 mmol), and Pd(dppf)Cl₂ (31.6 mg, 0.043mmol) in 1,4-dioxane (4 mL) was heated in a microwave at 130° C. for 45minutes to give(8-chloro-3-((trans-2-cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)boronicacid. LCMS (ESI): [M+H]⁺=316.0.

3-Bromo-4-ethylpyridine (143 mg, 0.77 mmol) and sodium carbonate (1mol/L) in water (2.14 ml, 2.139 mmol) were then added. The reactionmixture was heated in a microwave at 80° C. for 70 minutes. The organiclayer was purified with silica gel column chromatography (0 to 7%methanol in dichloromethane) to give(±)-trans-N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(141 mg, 87.4% yield). LCMS (ESI) [M+H]⁺=377.0.

Step 2: (±)-tert-butyl(3-((trans-2-cyanocyclopropane-1-carboxamido)-6-(4-ethylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture of(±)-trans-N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(141 mg, 0.374 mmol), tert-butyl carbamate (224 mg, 1.871 mmol),Pd₂(dba)₃ (34.2 mg, 0.037 mmol), Brettphos (21.14 mg, 0.037 mmol), andtBuONa (71.9 mg, 0.748 mmol) in 1,4-dioxane (5 mL) was stirred under Arat 120° C. for 2 hours. The reaction was concentrated to dryness. Theresidue was purified by silica-gel column chromatography (0 to 8%methanol in dichloromethane) to give the title compound (150 mg, 88%yield). LCMS (ESI) [M+H]⁺=458.0.

Step 3:(±)-trans-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of (±)-tert-butyl(3-((trans-2-cyanocyclopropane-1-carboxamido)-6-(4-ethylpyridin-3-yl)isoquinolin-8-yl)carbamate(150 mg, 0.327 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroaceticacid (0.3 mL) was stirred at 25° C. for 1.5 hours. The mixture wasconcentrated and purified by reverse phase prep-HPLC to affordtrans-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(16.8 mg, 14.3% yield) as solid. LCMS (ESI) R_(T) (min)=2.999,[M+H]⁺=358.1, method=T. ¹H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.34 (s,1H), 8.49 (d, J=5.1 Hz, 1H), 8.40-8.34 (m, 1H), 8.23 (s, 1H), 7.41-7.35(m, 1H), 6.88 (s, 1H), 6.55 (d, J=1.5 Hz, 1H), 6.38 (s, 2H), 2.80-2.72(m, 1H), 2.61 (q, J=7.5 Hz, 2H), 2.13 (ddd, J=9.3, 6.1, 4.3 Hz, 1H),1.59 (ddd, J=8.6, 6.0, 4.4 Hz, 1H), 1.43 (ddd, J=9.3, 5.9, 4.4 Hz, 1H),1.09 (t, J=7.6 Hz, 3H).

Example 52(±)-cis-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 68)

Step 1:(±)-cis-N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of(±)-cis-N-(6-bromo-8-chloroisoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(125 mg, 0.357 mmol), bis(pinacolato)diboron (139 mg, 0.535 mmol),potassium acetate (105 mg, 1.07 mmol), and Pd(dppf)Cl₂ (26.4 mg, 0.0357mmol) in 1,4-dioxane (2 mL) was heated in a microwave at 130° C. for 45minutes to give(8-chloro-3-((cis-2-cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)boronicacid. LCMS (ESI): [M+H]⁺=316.0.

3-Bromo-4-ethylpyridine (127 mg, 0.685 mmol) and sodium carbonate (1 M)in water (1.71 ml, 1.71 mmol) were then added. The reaction mixture washeated in a microwave at 80° C. for 2 hours. The organic layer waspurified with silica gel column chromatography (0 to 10% methanol indichloromethane) to give(±)-(cis-N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(81.5 mg, 63.2% yield). LCMS (ESI) [M+H]⁺=377.0.

Step 2: (±)-tert-butyl(3-((cis-2-cyanocyclopropane-1-carboxamido)-6-(4-ethylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture of(±)-(cis-N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(81.5 mg, 0.216 mmol), tert-butyl carbamate (129 mg, 1.08 mmol),Pd₂(dba)₃ (9.90 mg, 0.0108 mmol), Brettphos (6.11 mg, 0.0108 mmol), andtBuONa (31.2 mg, 0.324 mmol) in 1,4-dioxane (4.5 mL) was stirred underAr at 90° C. for 2.5 hours. The mixture was extracted withdichloromethane (30 mL×2). The organic extracts were washed with water(20 mL), brine (20 ml), dried over Na₂SO₄, filtered and concentrated togive the title compound (96 mg, 97.0% yield). LCMS (ESI) [M+H]⁺=458.0.

Step 3:(±)-cis-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of (±)-tert-butyl(3-((cis-2-cyanocyclopropane-1-carboxamido)-6-(4-ethylpyridin-3-yl)isoquinolin-8-yl)carbamate(96 mg, 0.210 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroaceticacid (0.3 mL) was stirred at 25° C. for 50 minutes. The mixture wasconcentrated and purified by reverse phase prep-HPLC to afford(±)-(cis-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(3.6 mg, 4.5% yield) as a solid. LCMS (ESI) R_(T) (min)=2.745,[M+H]⁺=358.2, method=T. ¹H NMR (400 MHz, DMSO) δ 11.06 (d, J=20.0 Hz,1H), 9.34 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.37 (d, J=0.5 Hz, 1H), 8.30(s, 1H), 7.38 (dt, J=9.0, 4.5 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J=1.5 Hz,1H), 6.37 (s, 2H), 2.62 (dt, J=15.0, 7.5 Hz, 3H), 2.30-2.22 (m, 1H),1.51-1.40 (m, 2H), 1.09 (t, J=7.6 Hz, 3H).

Example 53(±)-trans-N-(8-amino-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 69)

Step 1:(±)-trans-N-(8-chloro-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloroisoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(125 mg, 0.571 mmol), bis(pinacolato)diboron (222 mg, 0.856 mmol),potassium acetate (168 mg, 1.711 mmol), and Pd(dppf)Cl₂ (42.2 mg, 0.0571mmol) in 1,4-dioxane (3 mL) was heated in a microwave at 130° C. for 45minutes to give(±)-(8-chloro-3-((trans-2-cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)boronicacid. LCMS (ESI): [M+H]⁺=316.0.

5-Bromo-4-methylpicolinonitrile (168 mg, 0.856 mmol) and sodiumcarbonate (1 mol/L) in water (2.85 ml, 2.852 mmol) were then added. Thereaction mixture was heated in a microwave at 90° C. for 55 minutes. Theorganic layer was purified with silica gel column chromatography (0.5 to9% methanol in dichloromethane) to give(±)-(trans-N-(8-chloro-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(187 mg, 86.5% yield). LCMS (ESI) [M+H]⁺=388.0.

Step 2: (±)-tert-butyl(6-(6-cyano-4-methylpyridin-3-yl)-3-((trans-2-cyanocyclopropane-1-carboxamido)isoquinolin-8-yl)carbamate

A mixture of(±)-(trans-N-(8-chloro-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(160 mg, 0.413 mmol), tert-butyl carbamate (247 mg, 2.063 mmol),Pd₂(dba)₃ (37.8 mg, 0.041 mmol), Brettphos (23.3 mg, 0.041 mmol), andtBuONa (59.5 mg, 0.619 mmol) in 1,4-dioxane (10 mL) was stirred under Arat 80° C. for 1.5 hours. The reaction was concentrated to dryness. Theresidue was purified by silica gel column chromatography (0.5 to 8%methanol in dichloromethane) to give the title compound (45 mg, 23.3%yield). LCMS (ESI) [M+H]⁺=469.0.

Step 3:(±)-trans-N-(8-amino-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of (±)-tert-butyl(6-(6-cyano-4-methylpyridin-3-yl)-3-((trans-2-cyanocyclopropane-1-carboxamido)isoquinolin-8-yl)carbamate(45 mg, 0.096 mmol) and TFA (0.3 mL) in dichloromethane (4 mL) wasstirred at 25° C. for 1.5 hours. The mixture was concentrated andpurified by reverse phase prep-HPLC to afford(±)-trans-N-(8-amino-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(16.5 mg, 45.2% yield) as solid. LCMS (ESI) R_(T) (min)=4.401,[M+H]⁺=369.1, method=T. ¹H NMR (400 MHz, DMSO) δ 11.06 (d, J=20.0 Hz,1H), 9.34 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.37 (d, J=0.5 Hz, 1H), 8.30(s, 1H), 7.38 (dt, J=9.0, 4.5 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J=1.5 Hz,1H), 6.37 (s, 2H), 2.62 (dt, J=15.0, 7.5 Hz, 3H), 2.30-2.22 (m, 1H),1.51-1.40 (m, 2H), 1.09 (t, J=7.6 Hz, 3H).

Example 54(±)-trans-N-(8-amino-6-(6-cyano-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 70)

Step 1:(±)-trans-N-(8-chloro-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloroisoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(98 mg, 0.279 mmol), bis(pinacolato)diboron (109 mg, 0.419 mmol),potassium acetate (82.3 mg, 0.839 mmol), and Pd(dppf)Cl₂ (20.7 mg, 0.028mmol) in 1,4-dioxane (3 mL) was heated in a microwave at 130° C. for 45minutes to give(±)-(8-chloro-3-(trans-2-cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)boronicacid. LCMS (ESI): [M+I-I]⁺=316.0.

7-Bromo-8-methylpyrido[2,3-b]pyrazine (93.9 mg, 0.419 mmol) and sodiumcarbonate (1 M) in water (1.398 ml, 1.398 mmol) were then added. Thereaction mixture was heated in a microwave at 90° C. for 55 minutes. Theorganic layer was purified with silica gel column chromatography (0.5 to9% methanol in dichloromethane) to give(±)-trans-N-(8-chloro-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(73 mg, 55.3% yield). LCMS (ESI) [M+H]⁺=415.0.

Step 2: (±)-tert-butyl(3-(trans-2-cyanocyclopropane-1-carboxamido)-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-8-yl)carbamate

A mixture of(±)-trans-N-(8-chloro-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(67 mg, 0.0.1615 mmol), tert-butyl carbamate (96.5 mg, 0.807 mmol),Pd₂(dba)₃ (14.8 mg, 0.016 mmol), Brettphos (9.12 mg, 0.016 mmol), andtBuONa (23.3 mg, 0.242 mmol) in 1,4-dioxane (4 mL) was stirred under Arat 80° C. for 1.5 hours. The reaction was concentrated to dryness. Theresidue was purified by silica gel column chromatography (0.5 to 8%methanol in dichloromethane) to give the title compound (19 mg, 23.7%yield). LCMS (ESI) [M+H]⁺=496.0.

Step 3:(±)-trans-N-(8-amino-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide

A mixture of (±)-tert-butyl(3-(trans-2-cyanocyclopropane-1-carboxamido)-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-8-yl)carbamate(19 mg, 0.038 mmol) in dichloromethane (4 mL) and TFA (0.3 mL) wasstirred at 25° C. for 1 hour. The mixture was concentrated and purifiedby reverse phase prep-HPLC to afford(±)-trans-N-(8-amino-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(4.2 mg, 28% yield) as solid. LCMS (ESI) R_(T) (min)=3.847,[M+H]⁺=396.1, method=T. ¹H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.40 (s,1H), 9.17 (t, J=1.5 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 9.07 (s, 1H), 8.29(s, 1H), 7.08 (s, 1H), 6.71 (d, J=1.5 Hz, 1H), 6.47 (s, 2H), 2.82-2.73(m, 4H), 2.14 (ddd, J=9.3, 6.1, 4.3 Hz, 1H), 1.59 (ddd, J=8.6, 6.0, 4.5Hz, 1H), 1.43 (ddd, J=9.2, 5.9, 4.4 Hz, 1H).

Example 55(±)-trans-N-(8-amino-6-(6-methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 109)

Step 1: N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine

A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.0 g, 4.2 mmol),2,4-dimethoxybenzylamine (2.0 g, 12.6 mmol), and DIEA (1.6 g, 12.6 mmol)in 1,4-dioxane (5 mL) was heated at 110° C. for 16 h under Ar gas. Thereaction was concentrated to dryness. The crude product was purified byflash chromatography (Biotage, 20 g column, PE/EA=5:1) to giveN-[(2,4-dimethoxyphenyl)methyl]-4-iodo-5-methyl-pyridin-2-amine (1.0 g,61% yield) as a yellow solid. LCMS (ESI) [M+H]+=250.0.

Step 2: 4-iodo-5-methylpyridin-2-amine

To a mixture ofN-[(2,4-dimethoxyphenyl)methyl]-4-iodo-5-methyl-pyridin-2-amine (1.0 g,2.6 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroaceticacid (5 mL). Then the mixture was stirred overnight. The mixture wasthen concentrated. A 7N NH₃ solution in MeOH was added to adjust themixture to pH 8 and the mixture was concentrated. The crude product waspurified by flash chromatography (PE/EA=2:1) to give4-iodo-5-methyl-pyridin-2-amine (590 mg, 97% yield) as a yellow solid.LCMS (ESI) [M+H]⁺=235.7.

Step 3: 7-iodo-6-methylimidazo[1,2-a]pyridine

A mixture of 4-iodo-5-methyl-pyridin-2-amine (1.0 g, 4.3 mmol),chloroacetaldehyde (0.42 mL, 6.41 mmol), and NaHCO₃ (430 mg, 5.13 mmol)in ethanol (4 mL) and water (1 mL) was heated to 100° C. and stirredovernight. The mixture was concentrated. The residue was purified byflash column chromatography (DCM/MeOH=20/1) to give the product7-iodo-6-methyl-imidazo[1,2-a]pyridine (1.0 g, 90% yield) as yellowsolid. LCMS (ESI) [M+H]⁺=259.7.

Step 4:8-chloro-6-(6-methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-amine

A solution of 7-iodo-6-methyl-imidazo[1,2-a]pyridine (150 mg, 0.58mmol),8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine(442 mg, 1.45 mmol), Pd(dppf)Cl₂ (42 mg, 0.06 mmol), Na₂CO₃ (183 mg,1.74 mmol), and water (1 mL) in tetrahydrofuran (10 mL) was heated to65° C. for 3 h under N₂. Water (10 mL) was added. The mixture wasextracted with ethyl acetate (10 mL×2). The organic layer was washedwith water (20 mL×3), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatography(DCM/MeOH=15:1) to give8-chloro-6-(6-methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-amine (180mg, 77% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=309.7.

Step 5:(±)-trans-N-(8-chloro-6-(6-methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of (±)-trans-2-cyanocyclopropanecarboxylic acid (120 mg,1.08 mmol) in dichloromethane (5mL) and N,N-dimethylformamide (0.02 mL)was added ethanedioyl dichloride (274 mg, 2.16 mmol) at 0° C. Thereaction was stirred at 25° C. for 2 h. The mixture was concentrated togive crude product (±)-trans-2-cyanocyclopropanecarbonyl chloride (130mg, 1 mmol, 93% yield) as a yellow oil. To a solution of8-chloro-6-(6-methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-amine (180mg, 0.58 mmol) in dichloromethane (15 mL) and pyridine (0.14 mL, 1.75mmol) was added (±)-trans-2-cyanocyclo propanecarbonyl chloride (113 mg,0.87 mmol). The mixture was stirred at 25° C. for 30 min. The mixturewas concentrated and water (10 mL) was added. 1 N HCl was then added toadjust the mixture to a pH of 6. The mixture was extracted with DCM (10mL×3). The organic layer was washed with brine (20 mL×1), dried overNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography (PE/EA=2:1) to give the producttrans-N-[8-chloro-6-(6-methylimidazo[1,2-a]pyridin-7-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 85% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=402.7.

Step 6:(±)-trans-N-(8-amino-6-(6-methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of Pd₂(dba)₃ (45 mg, 0.05 mmol), xantphos (57 mg, 0.1 mmol),Cs₂CO₃ (243 mg, 0.75 mmol),(±)-trans-N-[8-chloro-6-(6-methylimidazo[1,2-a]pyridin-7-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (100 mg, 0.25 mmol) and tert-butyl carbamate (291 mg, 2.49mmol) in toluene (0.5mL) and N,N-dimethylformamide (0.5 mL) was heatedto 130° C. for 16 h in a sealed tube. The reaction mixture was cooled tort, diluted with ethyl acetate, washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was washed with PE and ethylacetate to give the crude product. The crude product was purified byprep-HPLC (Column Xbridge 21.2*250 mm c18, 10 μm. Mobile Phase A:water(10 mMol/LNH₄HCO₃) B:ACN) to give the product(±)-trans-N-[8-amino-6-(6-methylimidazo[1,2-a]pyridin-7-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(5 mg, 5.3% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.646,[M+H]⁺=383.7. Method=C; ¹H NMR(400 MHz, CD₃OD) δ 9.26 (s, 1H), 8.37 (s,1H), 8.30 (s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.04 (s,1H), 6.74 (s, 1H), 2.66-2.64 (m, 1H), 2.27 (s, 3H), 2.15-2.10 (m, 1H),1.61-1.57 (m, 2H).

Example 565-(8-amino-3-(trans-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-N,1-dimethyl-1H-pyrazole-3-carboxamide(Compound 110)

Step 1: 5-bromo-N,1-dimethyl-1H-pyrazole-3-carboxamide

A mixture of ethyl 5-bromo-1-methyl-pyrazole-3-carboxylate (300 mg, 1.29mmol) and methanamine in MeOH (10 mL, 12.87 mmol) was heated to 80° C.and stirred overnight. The reaction solution was concentrated to givethe product 5-bromo-N,1-dimethyl-pyrazole-3-carboxamide (280 mg, 99%yield) as a colorless oil. LCMS (ESI) [M+H]+=218.2

Step 2:5-(3-amino-8-chloroisoquinolin-6-yl)-N,1-dimethyl-1H-pyrazole-3-carboxamide

To a sealed tube was added 5-bromo-N,1-dimethyl-pyrazole-3-carboxamide(200 mg, 0.92 mmol),8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine(698 mg, 2.29 mmol), Pd(dppf)Cl₂ (67 mg, 0.09 mmol), K₃PO₄ (193 mg, 0.92mmol) and NaOAc (225 mg, 2.75 mmol), acetonitrile (5 mL), water (1 mL).The mixture was bubbled with N₂ for 2 min, and stirred at 90° C. for 3h. The mixture was concentrated. The crude product was purified by flashchromatography (DCM/MeOH=15:1) to give5-(3-amino-8-chloro-6-isoquinolyl)-N,1-dimethyl-pyrazole-3-carboxamide(290 mg, 81% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=316.7.

Step 3:(±)-5-(8-chloro-3-(trans-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-N,1-dimethyl-1H-pyrazole-3-carboxamide

To a solution of trans-2-cyanocyclopropanecarboxylic acid (250 mg, 2.25mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.02 mL) wasadded ethanedioyl dichloride (571 mg, 4.5 mmol) at 0° C. The reactionwas stirred at 25° C. for 2 h. The mixture was concentrated by rotavapto give crude (±)-trans-2-cyanocyclopropanecarbonyl chloride (290 mg,99% yield) as a yellow oil. To a solution of5-(3-amino-8-chloro-6-isoquinolyl)-N,1-dimethyl-pyrazole-3-carboxamide(230 mg, 0.73 mmol) in dichloromethane (15 mL) and pyridine (0.18 mL,2.19 mmol) was added the (±)-trans-2-cyanocyclopropane carbonyl chloride(141 mg, 1.09 mmol). The mixture was stirred at 25° C. for 30 min. Themixture was concentrated and water (10 mL) was added. 1 N HCl was addedto adjust the mixture to pH 6. The mixture was extracted with DCM (10mL×3). The organic layer was washed with brine (20 mL×1), dried overNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography (DCM/MeOH=15:1) to give the product(±)-5-[8-chloro-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-N,1-dimethyl-pyrazole-3-carboxamide(280 mg, 94% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=409.7.

Step 4:5-(8-amino-3-(trans-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-N,1-dimethyl-1H-pyrazole-3-carboxamide

A mixture of Pd₂dba₃ (44 mg, 0.05 mmol), xantphos (56 mg, 0.1 mmol),Cs₂CO₃ (239 mg, 0.73 mmol),5-[8-chloro-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-N,1-dimethyl-pyrazole-3-carboxamide(100 mg, 0.24 mmol) and tert-butyl carbamate (286 mg, 2.45 mmol) intoluene (0.5mL) and N,N-dimethylformamide (0.5mL) was heated to 130° C.for 16 h in a sealed tube. The reaction mixture was cooled to rt,diluted with EA, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was washed with PE and ethyl acetate to givethe crude product, which was purified by prep-HPLC (Column Xbridge21.2*250 mm c18, 10 μm. Mobile Phase A:water (10 mMol/L NH₄HCO₃) B:CAN,to give the product(±)-5-[8-amino-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-N,1-dimethyl-pyrazole-3-carboxamide(17 mg, 17.8% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.543,[M+H]⁺=390.7. Method=C; ¹H NMR(400MHz, CD₃OD) δ 9.25 (s, 1H), 8.32 (s,1H), 7.15 (s, 1H), 6.84 (s, 1H), 6.80 (d, J=1.2 Hz, 1H), 3.99 (s, 3H),2.93 (s, 3H), 2.65-2.62 (m, 1H), 2.15-2.10 (m, 1H), 1.62-1.48 (m, 2H).

Example 57(±)-trans-N-[8-amino-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 113)

Step 1:(±)-trans-N-(8-chloro-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(300 mg, 0.68 mmol), Pd(PPh3)4 (75 mg, 0.06 mmol) and Zn(CN)(44 mg, 0.38mmol) in N,N-dimethylformamide (14 mL) was stirred at 130° C. for 3 h.The mixture was purified by preparative reverse phase HPLC (C-18,acetonitrile/water+0.05% NH₄HCO₃), to give(±)-trans-N-[8-chloro-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(190 mg, 24% yield) as a white solid. LCMS (ESI) [M+H]⁺=388.1.

Step 2:(±)-trans-N-[8-(benzhydrylideneamino)-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(190 mg, 0.16 mmol), Pd₂(dba)₃ (28 mg, 0.03 mmol), Xantphos (37 mg, 0.06mmol), Cs₂CO₃ (107 mg, 0.33 mmol) and benzophenone imine (100 mg, 0.55mmol) in N,N-dimethylformamide (7 mL) and toluene (7 mL) under Ar wasstirred at 130° C. for 2.5 h. EtOAc (200 mL) was added. The mixture waswashed with H₂O (3×50 mL), brine (50 mL), dried with Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified bypreparative reverse phase HPLC (C-18, acetonitrile/water+0.05% NH₄HCO₃)to give(±)-trans-N-[8-(benzhydrylideneamino)-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(36 mg, 17% yield) as a white solid. LCMS (ESI) [M+H]⁺=533.3.

Step 3:(±)-trans-N-[8-amino-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(36 mg, 0.04 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in acetonitrile(10 mL) and water (10 mL) was stirred at 25° C. for 2 h. The reactionmixture was neutralized with NH₄OH (aq., 37%) to pH=7-8. The mixture wasconcentrated and purified by preparative reverse phase HPLC (C-18,acetonitrile/water+0.05% NH₄HCO₃) to give(±)-trans-N-[8-amino-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(11 mg, 72% yield) as a white solid. LCMS (ESI) R_(T) (min)=1.593,[M+H]+=369.1, Method=G. 1H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 9.57(s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.44 (s,2H), 7.40 (d, J=5.2 Hz, 1H), 6.93 (s, 1H), 2.78-2.75 (m, 1H), 2.21 (s,3H), 2.19-2.14 (m, 1H), 1.64-1.60 (m, 1H), 1.46-1.42 (m, 1H).

Example 58trans-N-[8-amino-7-methyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 115)

Step 1: 7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine

A mixture of 7-bromo-8-chloro-6-iodo-isoquinolin-3-amine (3.6 g, 9.39mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(2.5 g, 11.41 mmol), Pd(PPh₃)₄ (750 mg, 0.65 mmol), K₂CO₃ (3.8 g, 27.54mmol) in 1,4-dioxane (160 mL), water (40 mL) was stirred at 70° C. underAr for 23 h. The reaction mixture was cooled to room temperature, ethylacetate was added (500 mL), and the mixture washed with brine (100 mL).The organic layer was separated, dried over Na₂SO₄, filtered andevaporated. The residue was purified with silica-gel columnchromatography (PE:EA=1:2 to EA, Rf=0.5 at PE/EA 1/2) to afford7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (2.9 g, 89%yield) as a yellow solid. LCMS (ESI) [M+H]⁺=348.0.

Step2:(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

(COCl)2 (3.0 g, 23.62 mmol) was added dropwise to a suspension of(±)-trans-2-cyanocyclopropane carboxylic acid (1.2 g, 10.8 mmol) at 0°C. and the mixture was stirred at 0° C. for another 1 h. The mixture wasevaporated at room temperature to remove the unreacted (COCl)2. Theresidue was suspended in DCM (5 mL) and was added dropwise to a mixtureof 7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (2.9 g,8.32 mmol) and pyridine (10 mL, 123.64 mmol) in dichloromethane (50 mL)at 0° C. The reaction mixture was stirred at 0° C. for another 0.5 h. Tothe reaction mixture was added DCM (100 mL) and it was washed with H₂O(50 mL). The organic layer was separated, dried over Na₂SO₄, filteredand evaporated. The residue was purified with silica-gel columnchromatography (PE:EA=1:1 to 1:2, Rf=0.4 at PE/EA 1/1) to afford(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(2.85 g, 78% yield) as a light brown solid. LCMS (ESI) [M+H]⁺=441.0.

Step 3:(±)-trans-N-[8-chloro-7-methyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 0.45 mmol), trimethylboroxine (250 mg, 1.99 mmol), PdCl₂dppf(60 mg, 0.08 mmol), and K₂CO₃ (200 mg, 1.45 mmol) in 1,4-dioxane (10 mL)and water (2.5 mL) was stirred at 80° C. under Ar in sealed tube for 18h. The reaction mixture was cooled to room temperature, ethyl acetateadded (100 mL) and washed with brine (30 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and evaporated. The residue waspurified with silica-gel column chromatography (PE:EA=2:1 to 3:2 to 1:1)to afford(±)-trans-N-[8-chloro-7-methyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(50 mg, 29% yield) as a white solid. LCMS (ESI) [M+H]⁺=377.1.

Step 4: (±)-tert-butylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-7-methyl-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate

A mixture of(±)-trans-N-[8-chloro-7-methyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(25 mg, 0.07 mmol), tert-butyl carbamate (75 mg, 0.64 mmol), Pd₂dba₃ (20mg, 0.02 mmol), Brettphos (20 mg, 0.04 mmol), and t-BuONa (2M in THF,0.08 mL, 0.16 mmol) in 1,4-dioxane (2 mL) was stirred at 90° C. under Arfor 2 h. The reaction mixture was cooled to room temperature. To theresidue was added ethyl acetate (30 mL) and washed with sat. NH₄Cl (10mL). The ethyl acetate layer was separated, dried over Na₂SO₄, filteredand evaporated. The residue was purified with prep-TLC (EA:PE=3:2) toafford (±)-tert-butylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-7-methyl-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(7 mg, 23.1% yield) as white solid. LCMS (ESI) [M+H]⁺=458.2.

Step 5:(±)-trans-N-[8-amino-7-methyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of (±)-tert-butylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-7-methyl-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(7 mg, 0.02 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) anddichloromethane (2 mL) was stirred at 25° C. for 2 h. The reactionmixture was evaporated. The residue was dissolved in MeOH (1 mL), 7NNH₃/MeOH added until pH 9-10, and then purified by flash columnchromatography (C18, NH₄HCO_(3/)MeOH/H₂O) to give(±)-trans-N-[8-Amino-7-methyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(3 mg, 54.9% yield) as a light brown solid. LCMS (ESI): R_(T)(min)=1.70, [M+H]⁺=358.1, Method=C; ¹H NMR (400 MHz, CD₃OD) δ 9.31 (s,1H), 8.45 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.42 (d, J=5.2Hz, 1H), 6.90 (s, 1H), 2.66-2.62 (m, 1H), 2.16 (s, 3H), 2.13-2.08 (m,1H), 1.98 (s, 3H), 1.61-1.52 (m, 2H).

Example 59(±)-trans-N-[8-amino-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 116)

Step 1:(±)-trans-N-[8-chloro-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

The reaction mixture of[8-chloro-3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]boronicacid and(±)-trans-N-[8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(5 mL, about 0.43 mmol) was added 3-bromo-N,N-dimethyl-pyridin-4-amine(150 mg, 0.75 mmol), PdCl₂dppf (50 mg, 0.07 mmol), K₂CO₃ (150 mg, 1.09mmol) and water (1.5 mL). The reaction was then stirred at 80° C. underAr for 1 h. The reaction mixture was cooled to room temperature, ethylacetate added (40 mL) and washed with brine (15 mL). The organic layerwas separated, dried over Na₂SO₄, filtered and evaporated. The residuewas purified with silica-gel column chromatography (PE:DCM:EA=1:1:1 to1:1:0) to give(±)-trans-N-[8-chloro-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(80 mg, 48% yield) as a brown solid. LCMS (ESI) [M+H]⁺=392.1.

Step 2:(±)-trans-N-[8-(benzhydrylideneamino)-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(80 mg, 0.20 mmol), benzophenone imine (210 mg, 1.16 mmol), Pd₂dba₃ (40mg, 0.04 mmol), Xantphos (50 mg, 0.09 mmol), and Cs₂CO₃ (120 mg, 0.37mmol) in N,N-dimethylformamide (2 mL) and toluene (2 mL) was stirred at130° C. under Ar for 4 h. The reaction mixture was cooled to roomtemperature and ethyl acetate (50 mL) was added. The mixture washed withbrine (15 mL). The ethyl acetate layer was separated, dried over Na₂SO₄,filtered and evaporated. The residue was purified with silicachromatography (PE:EA=1:1 to 1:3) to give(±)-trans-N-[8-(benzhydrylideneamino)-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(45 mg, 41% yield) as a brown solid. LCMS (ESI) [M+H]⁺=537.2.

Step 3:(±)-trans-N-[8-amino-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(45 mg, 0.08 mmol) in 2,2,2-trifluoroacetic acid (1 mL), dichloromethane(2 mL) and water (0.5 mL) was stirred at 25° C. for 20 min. The residuewas dissolved in MeOH (1 mL). To the mixture was added 7N NH₃/MeOH untilpH 9-10. The mixture was then concentrated. The residue was purifiedwith prep-TLC (EA:MeOH=20:1) to give(±)-trans-N-[8-amino-6-[4-(dimethylamino)-3-pyridyl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(18.8 mg, 60% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.64,[M+H]⁺=373.2, method=NMR (400 MHz, CD₃OD) δ 9.21 (s, 1H), 8.26 (s, 1H),8.17 (d, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.07 (s, 1H), 6.93 (d, J=6.0 Hz,1H), 6.80 (d, J=1.2 Hz, 1H), 2.77 (s, 6H), 2.65-2.62 (m, 1H), 2.14-2.09(m, 1H), 1.62-1.52 (m, 2H).

Example 60(±)-trans-N-(8-amino-6-(1-methyl-4-oxo-1,4-dihydropyridin-2-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 117)

Step 1: 2-(3-amino-8-chloroisoquinolin-6-yl)-1-methylpyridin-4(1H)-one

To a sealed tube was added (3-amino-8-chloro-6-isoquinolyl)boronic acid(371 mg, 1.67 mmol), 2-chloro-1-methyl-pyridin-4-one (200 mg, 1.39mmol), Pd(dppf)Cl₂ (101 mg, 0.14 mmol), K₃PO₄ (293 mg, 1.39 mmol), NaOAc(342 mg, 4.18 mmol), acetonitrile (20 mL) and water (2 mL). The mixturewas bubbled with N₂ for 2 min and stirred at 90° C. for 3 h. The mixturewas concentrated and purified by prep-TLC (DCM/MeOH=20/1) to give2-(3-amino-8-chloro-6-isoquinolyl)-1-methyl-pyridin-4-one (220 mg, 55%yield) as a yellow solid. LCMS (ESI): [M-56]⁺=286.0.

Step 2:(±)-trans-N-(8-chloro-6-(1-methyl-4-oxo-1,4-dihydropyridin-2-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of2-(3-amino-8-chloro-6-isoquinolyl)-1-methyl-pyridin-4-one (210 mg, 0.74mmol) and pyridine (0.18 mL, 2.2 mmol) in dichloromethane (15 mL) wasadded (±)-trans-2-cyanocyclopropanecarbonyl chloride (238 mg, 1.84mmol). The mixture was stirred at 25° C. for 30 min. The mixture wasthen concentrated and purified by flash chromatography (PE/EA=2:1) togive the(±)-trans-N-[8-chloro-6-(1-methyl-4-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(160 mg, 40% yield) as a yellow solid. LCMS (ESI): [M-56]⁺=379.1.

Step 3:(±)-trans-N-(8-amino-6-(1-methyl-4-oxo-1,4-dihydropyridin-2-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(1-methyl-4-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(70 mg, 0.18 mmol), xantphos (42 mg, 0.07 mmol), Pd₂dba₃ (33 mg, 0.04mmol), and Cs₂CO₃ (180 mg, 0.55 mmol) in DMF (3 mL) and toluene (3 mL)was heated to 130° C. for 2 h. The mixture was concentrated and purifiedby prep-HPLC to give(±)-trans-N-[8-amino-6-(1-methyl-4-oxo-2-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(11.4 mg, 17% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.310,[M+H]⁺=360.1, Method=G; ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.37(s, 1H), 8.27 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 6.99 (s, 1H), 6.54-6.51(m, 3H), 6.14 (dd, J=2.8, 7.6 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 3.41 (s,3H), 2.77-2.73 (m, 1H), 2.17-2.12(m, 1H), 1.62-1.57 (m, 1H), 1.45-1.41(m, 1H).

Example 61(±)-trans-N-(8-amino-6-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 118)

Step 1: 4-bromo-3-(ethoxymethyl)-5-methyl-1H-pyrazole

A mixture of ethyl 5-methyl-1H-pyrazole-3-carboxylate (4.0 g, 25.95mmol) and NBS (5.08 g, 28.54 mmol) in N,N-dimethylformamide (15 mL) wasstirred at room temperature for 16 h. The mixture was taken up in EtOAc(200 mL) and the organics were washed with saturated brine solution. Theorganics were then separated and dried (Na₂SO₄) before concentrated todryness. The crude was then purified by flash column chromatography(PE/EA=3/2) to give ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate(4.8 g, 79% yield) as a white solid. LCMS (ESI): [M+H]⁺=234.9.

Step 2:4-bromo-3-(ethoxymethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a stirred solution of TsOH—H₂O (490 mg, 2.57 mmol) and ethyl4-bromo-5-methyl-1H-pyrazole-3-carboxylate (3.0 g, 12.87 mmol) indichloromethane (50 mL) was added 3,4-dihydro-2h-pyran (2.17 g, 25.74mmol). The mixture was stirred at room temperature for 4 h. The mixturewas concentrated and purified by flash column chromatography (PE/EA=4/1)to give the product ethyl4-bromo-5-methyl-1-tetrahydropyran-2-yl-pyrazole-3-carboxylate (3.4 g,83% yield) as a yellow oil. ¹HNMR (400 MHz, CD₃OD) δ 5.52 (dd, J=2.8,9.6 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.01-3.96 (m, 1H), 3.77-3.71 (m,1H), 2.42-2.35 (m, 4H), 2.14-2.10 (m, 1H), 1.99-1.94 (m, 1H), 1.82-1.62(m, 3H), 1.40 (t, J=7.2 Hz, 3H).

Step 3:8-chloro-6-(3-(ethoxymethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-amine

To a sealed tube was added (3-amino-8-chloro-6-isoquinolyl)boronic acid(252 mg, 1.14 mmol), ethyl4-bromo-5-methyl-1-tetrahydropyran-2-yl-pyrazole-3-carboxylate (300 mg,0.95 mmol), Pd(dppf)₂Cl₂ (69 mg, 0.09 mmol), K₃PO₄ (199 mg, 0.95 mmol),NaOAc (232 mg, 2.84 mmol), acetonitrile (5 mL) and water (0.5 mL). Themixture was bubbled with N₂ for 20 min and stirred at 90° C. for 3 h.The reaction was concentrated and purified by prep-TLC (PE/EA=1:1) togive ethyl4-(3-amino-8-chloro-6-isoquinolyl)-5-methyl-1-tetrahydropyran-2-yl-pyrazole-3-carboxylate(320 mg, 75% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=415.1.

Step 4:(4-(3-amino-8-chloroisoquinolin-6-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol

A mixture of ethyl4-(3-amino-8-chloro-6-isoquinolyl)-5-methyl-1-tetrahydropyran-2-yl-pyrazole-3-carboxylate(310 mg, 0.75 mmol) in methyl alcohol (15 mL) was added NaBH₄ (282 mg,7.47 mmol) at 0° C. The mixture was stirred at rt for 5 h and water (2mL) was added to quench the reaction. The mixture was concentrated and asolution of DCM:MeOH (10:1, 10 mL) was added. The mixture was filteredand the filtrate was concentrated and purified by prep-TLC (100% EA) togive[4-(3-amino-8-chloro-6-isoquinolyl)-5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl]methanol(300 mg, 75% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=373.1.

Step 5:6-(3-((tert-butyldimethylsilyloxy)methyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-8-chloroisoquinolin-3-amine

A mixture of[4-(3-amino-8-chloro-6-isoquinolyl)-5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl]methanol(300 mg, 0.56 mmol), tert-butyldimethylchlorosilane (849 mg, 5.64 mmol),and TEA (1267 mg, 12.55 mmol) in dichloromethane (50 mL) was refluxedovernight. The mixture was concentrated and purified by prep-TLC(PE/EA=2/1) to give6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl]-8-chloro-isoquinolin-3-amine(210 mg, 72% yield) as a yellow oil. LCMS (ESI): [M+H]⁺=488.2.

Step 6:trans-N-(6-(3-((tert-butyldimethylsilyloxy)methyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-8-chloroisoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl]-8-chloro-isoquinolin-3-amine(200 mg, 0.41 mmol) in dichloromethane (15 mL) and pyridine (0.3 mL) wasadded (±)-trans-2-cyanocyclopropanecarbonyl chloride (132 mg, 1.03mmol). The mixture was stirred at 25° C. for 30 min. The mixture wasconcentrated and purified by prep-TLC(PE/EA=3:1) to give(±)-trans-N-[6-[3-[[tert-butyl(dimethyl)silyl]oxymthyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl]-8-chloro-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(150 mg, 60% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=580.3. Step 7:(±)-trans-N-(8-amino-6-(3-((tert-butyldimethylsilyloxy)methyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl]-8-chloro-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(140 mg, 0.24 mmol), xantphos (55 mg, 0.10 mmol), Pd₂dba₃ (44 mg, 0.05mmol), and Cs₂CO₃ (235 mg, 0.72 mmol) in N,N-dimethylformamide(1.5mL)/toluene(1.5 mL) was heated at 145° C. for 3 h. The mixture wasconcentrated and used in the next step without further purification.LCMS (ESI): [M+H]⁺=561.3.

Step 8:(±)-trans-N-(8-amino-6-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a sealed tube was added(±)-trans-N-[8-amino-6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(60 mg, 0.11 mmol), dichloromethane (5 mL) and 2,2,2-trifluoroaceticacid (1 mL) and the mixture was stirred at rt for 2 h. The mixture wasconcentrated and purified by prep-HPLC to give(±)-trans-N-[8-amino-6-[3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(9 mg, 23% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.268,[M+H]⁺=363.1, method=A; ¹H NMR (400 MHz, CD₃OD) δ 9.19 (s, 1H), 8.26 (s,1H), 7.12 (s, 1H), 6.85 (s, 1H), 4.63 (s, 2H), 2.67-2.62 (m, 1H), 2.38(s, 3H), 2.14-2.09 (m, 1H), 1.61-1.53 (m, 2H).

Example 62(±)-trans-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropanecarboxamide(Compound 119)

Step 1: (±)-trans-2-(hydroxymethyl)cyclopropanecarboxylic acid

To a vial was added methyl(±)-trans-2-(hydroxymethyl)cyclopropanecarboxylate (500 mg, 3.84 mmol),water (5 mL), tetrahydrofuran (5 mL), methyl alcohol (5 mL) and NaOH(700 mg, 17.5 mmol) and the mixture stirred at 40° C. for 2 hours. Themixture was concentrated and acidified to pH=3-4 with 2 N HCl. Theproduct was extracted with ethyl acetate (50 mL×2), washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give(±)-trans-2-(hydroxymethyl)cyclopropanecarboxylic acid (390 mg, 87%yield) as a pale-yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ: 3.40 (dd,J=5.2, 11.6 Hz, 1H), 3.22 (dd, J=5.6, 11.6 Hz, 1H), 1.41-1.35 (m, 2H),0.91-0.85 (m, 1H), 0.75-0.70 (m, 1H).

Step 2: (±)-trans-2-(acetoxymethyl)cyclopropanecarboxylic acid

To a vial was added (±)-trans-2-(hydroxymethyl)cyclopropanecarboxylicacid (390 mg, 3.36 mmol), dichloromethane (10 mL) and acetyl chloride (1mL, 14.14 mmol) and the mixture was stirred at 40° C. for 2 hours. Themixture was concentrated in vacuo to get(±)-trans-2-(acetoxymethyl)cyclopropanecarboxylic acid (530 mg, 90%yield) as a pale-yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.20 (s, 1H),3.99 (dd, J=6.0, 11.6 Hz, 1H), 3.83 (dd, J=7.2, 11.6 Hz, 1H), 2.02 (s,3H), 1.59-1.50 (m, 2H), 1.04-0.99 (m, 1H), 0.92-0.87 (m, 1H).

Step 3: (±)-trans-2-(chlorocarbonyl)cyclopropyl)methyl acetate

To a vial was added (±)-trans-2-(acetoxymethyl)cyclopropanecarboxylicacid (530 mg, 3.02 mmol) and DCM (30 mL) and cooled to 0° C. Oxalyldichloride (0.5 mL, 6.03 mmol) was added dropwise and thenN,N-dimethylformamide (0.01 mL, 0.13 mmol). The mixture was stirred at20° C. for 2 hours. The reaction mixture was concentrated in vacuo toafford a crude product that was used directly in the next step.

Step 4:(±)-trans-2-(8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)cyclopropyl)methylacetate

To a vial was added 8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine(200 mg, 0.74 mmol), TEA (0.8 mL, 5.69 mmol) and DCM (5 mL) and then asolution of (±)-trans-2-chlorocarbonylcyclopropyl)methyl acetate (650mg, 2.94 mmol) in DCM (5 mL) was added dropwise. The mixture was stirredat rt for 2 hours. The mixture was concentrated and purified by flashcolumn chromatography (PE/EA from 1:1 to 0:100) to get(±)-trans-[2-[[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]carbamoyl]cyclopropyl]methylacetate (220 mg, 72% yield) as white solid. LCMS (ESI): [M+H]⁺=410.1.

Step 5:(±)-trans-N-(8-(diphenylmethyleneamino)-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropanecarboxamide

To a sealed tube was added(±)-[trans-2-[[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]carbamoyl]cyclopropyl]methyl acetate (210 mg, 0.51 mmol), Xantphos (150 mg, 0.2600mmol), Pd₂(dba)₃ (150 mg, 0.16 mmol), Cs₂CO₃ (500 mg, 1.54 mmol),benzophenone imine (600 mg, 3.31 mmol) and N,N-dimethylformamide (10mL). The mixture was bubbled with N₂ for 2 min and then stirred at 130°C. for 4 hours. The mixture was concentrated at 100° C. to remove allorganic solvents. Methyl alcohol (20 mL) was added and the reaction wasstirred at 50° C. for 1 hour. The mixture was then filtered andconcentrated in vacuo. The residue was purified by column chromatography(PE/EA from 1:1 to 0:100) to give(±)-trans-N-[8-benzhydrylideneamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-(hydroxymethyl)cyclopropanecarboxamide (151 mg, 50% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=513.3.

Step 6:(±)-trans-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropanecarboxamide

To a vial was added(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-(hydroxymethyl)cyclopropanecarboxamide(150 mg, 0.25 mmol) and 2 N HCl (5 mL, 10 mmol). The mixture was stirredat rt for 2 h. The pH of the mixture was then adjusted to pH 7 with aq.NaHCO₃. The product was then extracted with DCM/MeOH=10:1 (100 mL×2).The organic extracts were concentrated in vacuo and purified bycombiflash (DCM/MEOH from 30:1 to 15:1) to get(±)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-(hydroxymethyl)cyclopropanecarboxamide(74 mg, 82% yield) as a yellow solid. The single enantiomers werefurther isolated by chiral SFC. LCMS (ESI) of racemate: R_(T)(min)=1.302, [M+H]⁺=349.2, method=B; ¹H NMR of racemate (400 MHz, CD₃OD)δ 9.24 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.39(d, J=5.2 Hz, 1H), 6.98 (s, 1H), 6.67 (d, J=1.6 Hz, 1H), 3.64 (dd,J=6.0, 11.2 Hz, 1H), 3.48 (dd, J=6.8, 11.2 Hz, 1H), 2.37 (s, 3H),1.92-1.85 (m, 1H), 1.77-1.66 (m, 1H), 1.28-1.21 (m, 1H), 0.97-0.90 (m,1H).

Example 63(±)-trans-N-[8-amino-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (Compound 122)

Step 1:(±)-trans-N-[8-chloro-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(350 mg, 1 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(300 mg, 1.14 mmol), Pd(dppf)Cl₂ (70 mg, 0.1 mmol), potassium phosphate(3 H₂O) (660 mg, 2.48 mmol) in 1,4-dioxane (9 mL) and water (1.5 mL) wasstirred at 100° C. for 3 h. The reaction was concentrated to dryness.The crude residue was then purified by silica gel column chromatography(ethyl acetate/petroleum etherl/13-1/1) to afford(±)-trans-N-[8-chloro-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(230 mg, 51% yield) as a white solid. LCMS (ESI): [M+H]⁺=406.1.

Step 2:(±)-trans-N-[8-chloro-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A solution of(±)-trans-N-[8-chloro-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 0.49 mmol) and 3,4-dihydro-2h-pyran (2.0 mL) in trifluoroaceticacid (0.5 mL) and dichloromethane (15 mL) was heated to reflux forovernight. The reaction was concentrated to dryness and the cruderesidue was then purified by column chromatography (ethylacetate/petroleum ether 1/5-1/3) to afford(±)-trans-N-[8-chloro-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(230 mg, 95% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=490.1.

Step3:(±)-trans-N-[8-(benzhydrylideneamino)-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.2 mmol), benzophenone imine (182 mg, 1.0 mmol), Xantphos (58mg, 0.1 mmol), Pd₂(dba)₃ (46.0 mg, 0.05 mmol) and Cs₂CO₃ (170.0 mg, 0.52mmol) in dry N,N-dimethylformamide (3.0 mL) and dry toluene (3.0 mL) wasstirred at 130° C. under inert atmosphere for 4 h. The reaction wasconcentrated to remove toluene and the residue was taken up in ethylacetate (15 ml). The organic mixture was washed with 20 mL of brine. Theorganics were then separated, dried (Na₂SO₄) and concentrated todryness. The crude product was then purified by column chromatography(ethyl acetate/petroleum ether, 1/3-1/1) to afford(±)-trans-N-[8-(benzhydrylideneamino)-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 57% yield) as a yellow liquid. LCMS (ESI): [M+H]⁺=635.2.

Step 4:(±)-trans-N-[8-amino-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A solution of(±)-trans-N-[8-(benzhydrylideneamino)-6-[1-tetrahydropyran-2-yl-3-(trifluoromethyl)pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (100 mg,0.11 mmol) in methyl alcohol (2 mL) and 4M HCl (2 mL, 8 mmol) wasstirred at room temperature for 1 h. Excess sodium bicarbonate wasadded. The mixture was then filtered. The filtrate was concentrated andpurified by reverse phase chromatography (methanol 60%/0.1% HCl inwater) to afford(±)-trans-N-[8-amino-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (8 mg, 18.2% yield) as a red solid (HCl salt). LCMS (ESI):[M+H]⁺=387.1, R_(T)(min)=1.69, Method=B; ¹H NMR (400 MHz,CD₃OD) δ 9.27(s, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.19 (s, 1H), 6.92 (s, 1H),2.63-2.61 (m, 1H), 2.20-2.15(m, 1H), 1.65-1.59(m, 2H).

Example 64(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 123)

Step 1:(±)-trans-N-(8-chloro-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]boronicacid (400 mg, 1.27 mmol), 7-bromo-8-methyl-pyrido[2,3-b]pyrazine (285mg, 1.27 mmol), PdCl₂dppf (93 mg, 0.13 mmol), and K₂CO₃ (525 mg, 3.8mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 100° C. for 3h under Ar. The reaction was concentrated to dryness. The residue waspurified by silica gel column chromatography (PE:EA=2:1 to PE:EA=1:1) togive the title compound as a yellow solid (300 mg, 38% yeild). LCMS(ESI) [M+H]+=415.2.

Step 2: (±)-tert-butyl3-((trans)-2-cyanocyclopropanecarboxamido)-6-(8-methylpyrido[3,2-]pyrazin-7-yl)isoquinolin-8-ylcarbamate

A mixture of(±)-trans-N-[8-chloro-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(290 mg, 0.7 mmol), tert-butyl carbamate (245 mg, 2.09 mmol), Pd₃(dba)₂(64 mg, 0.07 mmol), Brettphos (38 mg, 0.07 mmol), and Cs₂CO₃ (684 mg,2.1 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 2 h under Argas. The reaction was concentrated to dryness. The residue was purifiedby silica column chromatography (PE:EA=1:1 to PE:EA=1:2) to give thetitle compound as a yellow solid (190 mg, 49% yeild). LCMS (ESI)[M+H]+=496.3.

Step 3:(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of (±)-tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)-8-isoquinolyl]carbamate(190 mg, 0.38 mmol) and TFA (1 mL, 0.38 mmol) in dichloromethane (2 mL)was stirred at room temperature under N₂ gas. The reaction wasconcentrated to dryness and the residue was taken up in EtOAc (10 mL)and pH adjusted 7-8 with sat NaHCO₃. The organics were then separated,dried (NaSO₄) and concentrated to dryness. The residue was purified withsilica column chromatography (EA:PE=1:1 to EA:DCM=2:1) to give the titlecompound as a yellow solid (49.5 mg, 32% yeild). LCMS (ESI):RT(min)=1.65, [M+H]+=396.2, Method=B. ¹H NMR (400 MHz, DMSO-d₆) δ 11.15(s, 1H), 9.40 (s, 1H), 9.17 (d, J=1.6 Hz, 1H), 9.13 (d, J=1.6 Hz, 1H),9.06 (s, 1H), 8.29 (s, 1H), 7.08 (s, 1H), 6.71 (s, 1H), 6.48 (s, 2H),2.79-2.75 (m, 3H), 2.15-2.11 (m, 1H), 1.61-1.59 (m, 1H), 1.44-1.42 (m,1H).

Example 65(trans)-N-(8-amino-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 124)

Step 1:(±)-trans-N-(8-chloro-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(400 mg, 1.14 mmol), (4R)-4-methyloxazolidin-2-one (140 mg, 1.38 mmol),Pd₃(dba)₂ (105 mg, 0.11 mmol), Xantphos (66 mg, 0.11 mmol), and K₃PO₄(726 mg, 3.42 mmol) in 1,4-dioxane (5 mL) was heated at 90° C. for 3 hunder Ar. The reaction was concentrated to dryness. The residue waspurified by silica gel column chromatography (PE:EA=2:1 to PE:EA=1:1) togive the title compound as a yellow solid (350 mg, 83% yeild) in theend. LCMS (ESI) [M+H]+=371.1.

Step 2: tert-butyl3-(trans-2-cyanocyclopropanecarboxamido)-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-8-ylcarbamate

A mixture oftrans-N-[8-chloro-6-[(4R)-4-methyl-2-oxo-oxazolidin-3-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(340 mg, 0.92 mmol), tert-butyl carbamate (500 mg, 4.27 mmol), Pd₃(dba)₂(84 mg, 0.09 mmol), Brettphos (50 mg, 0.09 mmol) and Cs₂CO₃ (897 mg,2.75 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 3 h under Ar.The reaction was concentrated to dryness. The residue was purified withsilica gel column chromatography (PE:EA=2:1 to PE:EA=1:1) to give thetitle compound as a yellow solid (240 mg, 58% yeild) in the end. LCMS(ESI) [M+H]+=452.2.

Step 3:(trans)-N-(8-amino-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-[(4R)-4-methyl-2-oxo-oxazolidin-3-yl]-8-isoquinolyl]carbamate(240 mg, 0.53 mmol) and TFA (1 mL, 0.53 mmol) in dichloromethane (4 mL)was stirred for 2 h at room temperature under Ar gas. The reaction wasconcentrated to dryness and the residue was taken up in EtOAc (10 ml)and adjusted pH to 7-8 with sat NaHCO₃. The organics were thenseparated, dried (Na₂SO₄) and concentrated to dryness. The residue waspurified by silica gel column chromatography (EA:PE=1:1 to EA:DCM=2:1)to give the title product as a yellow solid. LCMS (ESI): RT(min)=1.56,[M+H]+=352.2, Method=B. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.21(s, 1H), 8.15 (s, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H),6.35 (s, 2H), 4.70-4.67 (m, 1H), 4.57-4.53 (m, 1H), 4.06-4.03 (m, 1H),2.75-2.73 (m, 1H), 2.14-2.10 (m, 1H), 1.60-1.58 (m, 1H), 1.42-1.38 (m,1H), 1.28 (d, J=6.0 Hz, 3H).

Example 66(1S,2S)—N-(8-amino-6-(2-methyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 125)

Step 1:(1S,2S)—N-(8-chloro-6-(2-methyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of 5-methyl-2-pyrrolidinone (87 mg, 0.88 mmol),(1S,2S)—N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(250 mg, 0.73 mmol), Xantphos (43 mg, 0.07 mmol), Pd₂(dba)₃ (67 mg, 0.07mmol), and K₃PO₄ (462 mg, 2.18 mmol) in 1,4-dioxane (10 mL) was heatedat 90° C. for 3 h under Ar. The reaction was concentrated to dryness.The residue was purified by silica gel column chromatography (EA:PE=1:1to EA:DCM=2:1) to give the title compound as a yellow solid (200 mg, 76%yeild). LCMS (ESI) [M+H]+=362.1.

Step 2: tert-butyl3-((1S,2S)-2-fluorocyclopropanecarboxamido)-6-(2-methyl-5-oxopyrrolidin-1-yl)isoquinolin-8-ylcarbamate

A mixture of(1S,2S)—N-[8-chloro-6-(2-methyl-5-oxo-pyrrolidin-1-yl)-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide(170 mg, 0.47 mmol), tert-butyl carbamate (550 mg, 4.69 mmol), Brettphos(53 mg, 0.1 mmol), Pd₂(dba)₃ (86 mg, 0.09 mmol) and Cs₂CO₃ (460 mg, 1.41mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 3 h under Ar. Thereaction was concentrated to dryness. The residue was purified withsilica gel column chromatography (PE:EA=1:1 to PE:EA =1:2) to give thetitle compound as a is yellow solid (140 mg, 59% yield). LCMS (ESI)[M+H]+=443.2

Step 3:(1S,2S)—N-(8-amino-6-(2-methyl-5-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-6-(2-methyl-5-oxo-pyrrolidin-1-yl)-8-isoquinolyl]carbamate(140 mg, 0.32 mmol) and TFA (0.5 mL, 0.32 mmol) in dichloromethane (2mL) was stirred at room temperature for 1 h. The reaction wasconcentrated to dryness. The residue was taken up in EtOAc (10 mL) andthe pH adjusted to 7-8 with sat NaHCO₃. The solution was concentratedand purified by silica gel chromatography (PE:EA=1:1 to EA) to give thetitle compound as a yellow solid (78.2 mg, 72% yield). LCMS (ESI):RT(min)=1.52, [M+H]+=343.1, Method=B. ¹HNMR (400 MHz, CD₃OD) δ 9.14 (s,1H), 8.11 (s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 4.98 (d, J=3.6Hz, 0.5H),4.82-4.81 (m, 0.5H), 4.51 (d, J=6.4Hz, 1H), 2.72-2.61 (m, 1H), 2.59-2.53(m, 1H), 2.48-2.41 (m, 1H), 2.16-2.14 (m, 1H), 1.88-1.78 (m, 2H),1.28-1.21 (m, 4H).

Example 67(±)-trans-N-(8-amino-7-fluoro-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 126)

Step 1:trans-N-(8-chloro-7-fluoro-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(330 mg, 0.79 mmol), (4R)-4-methyloxazolidin-2-one (160 mg, 1.58 mmol),CuI (151 mg, 0.79 mmol) and N1,N2-dimethylethane-1,2-diamine (71 mg,0.81 mmol) in 1,4-dioxane (15 mL) was heated at 90° C. for 3 h under Ar.The reaction was concentrated to dryness and purified by silica gelcolumn chromatography (PE:EA=2:1 to PE:EA=2:1) to give the titlecompound as a white solid (290 mg, 77% yield). LCMS (ESI) [M+H]+=345.0.

Step 2: tert-butyl3-((trans)-2-cyanocyclopropanecarboxamido)-7-fluoro-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-8-ylcarbamate

A mixture of tert-butyl carbamate (693 mg, 5.92 mmol),trans-N-[8-chloro-7-fluoro-6-[(4R)-4-methyl-2-oxo-oxazolidin-3-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(230 mg, 0.59 mmol), Pd₂(dba)₃ (270 mg, 0.3 mmol), Brettphos (158 mg,0.29 mmol) and Cs₂CO₃ (576 mg, 1.77 mmol) in 1,4-dioxane (8 mL) washeated at 90° C. for 3 h under Ar. The reaction was concentrated todryness and purified by silica gel column chromatography (PE:EA=2:1 toPE:EA=1:2) followed by prep-HPLC(eluent: 5%-95% methanol and 0.8 g/LNH₄HCO₃ in water) to give the title compound as a white solid (55 mg,14% yield). LCMS (ESI) [M+H]+=470.2.

Step 3:(trans)-N-(8-amino-7-fluoro-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-7-fluoro-6-[(4R)-4-methyl-2-oxo-oxazolidin-3-yl]-8-isoquinolyl]carbamate(55 mg, 0.12 mmol) and TFA (0.5 mL, 0.12 mmol) in dichloromethane (2 mL)was stirred at room temperature for 1 h. The reaction mixture waspurified with prep-HPLC (5-95% mentanol and 0.8g/L NH₄HCO₃ in water) togive the title compound (30.6 mg, 13.7% yield). LCMS (ESI):R_(T)(min)=1.65, [M+H]+=370.2, Method=B. ¹HNMR (400 MHz, DMSO-d₆) δ11.14 (s, 1H), 9.39 (s, 1H), 8.22 (s, 1H), 7.05 (d, J=6.4 Hz, 1H), 6.37(s, 2H), 4.67 (t, J=8.4Hz, 1H), 4.54-4.52 (m, 1H), 4.06 (t, J=8.0 Hz,1H), 2.77-2.76 (m, 1H), 2.14-2.12 (m, 1H), 1.60-1.56 (m, 1H), 1.44-1.42(m, 1H), 1.15 (d, J=6.0 Hz, 3H).

Example 68(±)-trans-N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 127)

Step 1:trans-N-(8-chloro-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(250 mg, 0.71 mmol), (4S)-4-methyloxazolidin-2-one (86 mg, 0.85 mmol),K₃PO₄ (453 mg, 2.14 mmol), Xanphos (42 mg, 0.07 mmol), and Pd₂(dba)₃ (66mg, 0.07 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 3 h underAr. The reaction was concentrated to dryness and purified by silica gelcolumn chromatography (PE:EA=4:1 to PE:EA=1:1) to give the titlecompound as a yellow solid (180 mg, 37% yield). LCMS (ESI) [M+H]+=371.1.

Step 2: tert-butyl3-((trans)-2-cyanocyclopropanecarboxamido)-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-8-ylcarbamate

A mixture of(trans)-N-[8-chloro-6-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (330 mg, 0.89 mmol), tert-butyl carbamate (520 mg, 4.44mmol), Brettphos (96 mg, 0.18 mmol), Pd₂(dba)₃ (162 mg, 0.18 mmol), andCs₂CO₃ (870 mg, 2.67 mmol) in 1,4-dioxane (10 mL) was heated at 90° C.for 3 h under Ar gas. The reaction was concentrated to dryness. Theresidue was purified with silica column chromatography (PE:EA=2:1 toPE:EA=1:1, Rf=0.4 at PE/EA 1/1). The product is yellow solid (220 mg,51% yeild) in the end. LCMS (ESI) [M+H]+=452.2

Step 3:trans-N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-8-isoquinolyl]carbamate(220 mg, 0.49 mmol) and TFA (0.5 mL, 0.49 mmol) in dichloromethane (2mL) was stirred at room temperature for 1 h. The reaction mixture waspurified by prep-HPLC (5%-95% methanol and 0.08 g/L NH₄HCO₃ in water) togive the title compound as a yellow solid (64.7 mg, 37.4% yield). LCMS(ESI): RT(min)=1.52, [M+H]+=352.1, Method=B. ¹HNMR (400 MHz, DMSO-d₆) δ11.03 (s, 1H), 9.20 (s, 1H), 8.15 (s, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.94(d, J=1.6 Hz, 1H), 6.35 (s, 2H), 4.70-4.67 (m, 1H), 4.57-5.54 (m, 1H),4.06-4.03 (m, 1H), 2.75-2.72 (m, 1H), 2.14-2.10 (m, 1H), 1.60-1.55 (m,1H), 1.44-1.40 (m, 1H), 1.28 (d, J=6.4 Hz, 3H).

Example 69((1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128)

Step 1:(1S,2S)—N-(8-chloro-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of(1S,2S)—N-(6-bromo-8-chloro-3-isoquinolyl)-2-fluoro-cyclopropanecarboxamide(200 mg, 0.58 mmol), (4S)-4-methyloxazolidin-2-one (71 mg, 0.7 mmol),Xantphos (34 mg, 0.06 mmol), Pd₂(dba)₃ (54 mg, 0.06 mmol) and K₃PO₄ (369mg, 1.74 mmol) in 1,4-dioxane (8 mL) was heated at 90° C. for 3 h underAr. The reaction was concentrated to dryness and purified with silicagel column chromatography (PE:EA=4:1 to PE:EA=1:1) to give the titlecompound as a yellow solid (140 mg, 58% yeild). LCMS (ESI) [M+H]⁺=364.1.

Step 2: tert-butyl3-((1S,2S)-2-fluorocyclopropanecarboxamido)-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-8-ylcarbamate

A mixture of(1S,2S)—N-[8-chloro-6-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-3-isoquinolyl]-2-fluoro-cyclopropanecarboxamide (140 mg, 0.38 mmol), tert-butyl carbamate (225 mg, 1.92mmol), Pd₂(dba)₃ (70 mg, 0.08 mmol), Brettphos (40 mg, 0.07 mmol) andCs₂CO₃ (375 mg, 1.15 mmol) in 1,4-dioxane (4 mL) was heated at 90° C.for 3 h under Ar. The reaction was concentrated to dryness and purifiedby silica column chromatography (PE:EA=2:1 to PE:EA=1:1) to give thetitle compound as a white solid (110 mg, 58% yeild). LCMS (ESI)[M+H]⁺=445.2

Step 3:(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-6-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-8-isoquinolyl]carbamate(110 mg, 0.25 mmol) and TFA (0.5 mL, 0.25 mmol) in dichloromethane (2mL) was stirred at room temperature for 1 h. The reaction was adjustedpH to 7-8 with sat NaHCO₃. The mixture was purified with prep-HPLC(5%-95% methanol and 0.8 g/L NH₄HCO₃ in water) to give the titlecompound as a brown solid (56.3 mg, 48.2% yeild). LCMS (ESI):RT(min)=1.47, [M+H]+=345.1, method=B. ¹HNMR (400 MHz, DMSO-d₆) δ 10.75(s, 1H), 9.19 (s, 1H), 8.19 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.93 (s,1H), 6.32 (s, 2H), 5.02-5.00(m, 0.5H), 4.84-4.83 (m, 0.5H), 4.72-4.67(m, 1H), 4.58-4.54 (m, 1H), 4.06-4.03 (m, 1H), 2.26-2.23 (m, 1H),1.69-1.63 (m, 1H), 1.28 (d, J=6.4Hz, 3H), 1.17-1.13 (m, 1H).

Example 70(±)-trans-N-(8-amino-6-(4-methylisothiazol-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 130)

Step 1:(±)-trans-N-(8-chloro-6-(4-methylisothiazol-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 0.5 mmol), 3-bromo-4-methyl-isothiazole (107 mg, 0.6 mmol),Pd(dppf)Cl₂ (73 mg, 0.1 mmol) and K₂CO₃ (138 mg, 1.0 mmol) in1,4-dioxane (10 mL) and water (1 mL) was stirred at 100° C. under N₂ for16 h. The mixture was concentrated and purified by flash columnchromatography eluting with 0-100% ethyl acetate in PE to give(±)-trans-N-[8-chloro-6-(4-methylisothiazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 54% yield) as a white solid. LCMS (ESI): [M+H]⁺=369.2.

Step 2: (±)-tert-butyl3-((trans-)-2-cyanocyclopropanecarboxamido)-6-(4-methylisothiazol-3-yl)isoquinolin-8-ylcarbamate

A mixture of(±)-trans-N-[8-chloro-6-(4-methylisothiazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(80 mg, 0.22 mmol), tert-butyl carbamate (508 mg, 4.34 mmol), Pd₂(dba)₃(39 mg, 0.04 mmol) and brettphos (46 mg, 0.09 mmol) in 1,4-dioxane (10mL) was stirred at 90° C. under N₂ for 1 hour. The mixture wasconcentrated and the residue was purified by flash column chromatographyeluting with 0-50% EA in PE to give (±)-tert-butylN-[3-[[(trans-)-2-cyanocyclopropanecarbonyl]amino]-6-(4-methylisothiazol-3-yl)-8-isoquinolyl]carbamate(60 mg, 62% yield) as a white solid. LCMS (ESI): [M+H]⁺=450.1.

Step 3:(±)-trans-N-(8-amino-6-(4-methylisothiazol-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of (±)-tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(4-methylisothiazol-3-yl)-8-isoquinolyl]carbamate(80 mg, 0.18 mmol) in dichloromethane (2 mL) was added TFA (2 mL). Themixture was stirred at 25° C. for 2 hours. The mixture was concentratedand basified with NH₃ in methanol (7M). The mixture was purified byreverse phase chromatography (acetonitrile 0-50/0.05% NH₄HCO₃ in water)to afford(±)-(trans+N-[8-amino-6-(4-methylisothiazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(36 mg, 58% yield) as a light yellow solid. LCMS (ESI): R_(T)(min)=1.698, [M+H]⁺=350.1, method=C; ¹H NMR (400 MHz,DMSO-d₆) δ 11.12(s, 1H), 9.33 (s, 1H), 8.81 (d, J=0.4Hz, 1H), 8.29 (s, 1H), 7.20 (s,1H), 6.97 (d, J=1.2 Hz, 1H), 6.37 (s, 2H), 2.78-2.73 (m, 1H), 2.42 (s,3H), 2.16-2.12 (m, 1H), 1.62-1.57 (m, 1H), 1.46-1.41 (m, 1H).

Example 71(±)-trans-N-(8-amino-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 131)

Step 1:trans-N-(8-chloro-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of (3R)-3-hydroxypyrrolidin-2-one (129 mg, 1.28 mmol),(trans-)-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(300 mg, 0.86 mmol), Pd₂(dba)₃ (83 mg, 0.09 mmol), xantphos (98 mg, 0.17mmol), and Cs₂CO₃ (556 mg, 1.71 mmol) in 1,4-dioxane (10 mL) was stirredat 100° C. for 2 h. The mixture was concentrated and purified by flashcolumn chromatography eluting with 0-20% MeOH in DCM to givetrans-N-[8-chloro-6-[(3R)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 47% yield) as a brown solid. LCMS (ESI): [M+H]⁺=371.1.

Step 2:trans-N-(8-amino-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-[8-chloro-6-[(3R)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(110 mg, 0.3 mmol), Pd₂(dba)₃ (28 mg, 0.03 mmol), brettphos (31 mg, 0.06mmol), t-BuONa (192 mg, 0.59 mmol) and tert-butyl carbamate (695 mg,5.93 mmol) in 1,4-dioxane (10 mL) was stirred at 90° C. for 2 h. Themixture was concentrated and purified by flash column chromatographyeluting with 0-20% MeOH in DCM to give tert-butylN-[3-[[(trans-)-2-cyanocyclopropanecarbonyl]amino]-6-[(3R)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-8-isoquinolyl]carbamate(62 mg, 28% yield) as a brown solid. LCMS (ESI): [M+H]⁺=452.0.

Step 3:trans-N-(8-amino-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of tert-butyl N-[3-[[(trans-)-2-cyanocyclopropanecarbonyl]amino]-6-[(3R)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-8-isoquinolyl]carbamate(50 mg, 0.11 mmol) in dichloromethane (3 mL) was added TFA (3 mL) andthe mixture was stirred at 25° C. for 2 hours. The mixture wasconcentrated and basified with NH₃ in methanol (7M), concentrated andthe resulting residue was purified by reverse phase chromatography(acetonitrile 0-70/0.1% NH₄HCO₃ in water) to affordtrans-N-[8-amino-6-[(3R)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(2 mg, 5.1% yield) as a brown solid. LCMS (ESI): R_(T) (min)=1.396,[M+H]⁺=352.1, Method=C; ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.20(s, 1H), 8.14 (s, 1H), 7.28(d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H),6.315(s, 2H), 5.78-5.77 (m, 1H), 4.34-4.28 (m, 1H), 3.82-3.71 (m, 1H),2.77-2.72(m, 1H), 2.44-2.33 (m, 1H), 2.15-2.10 (m, 1H), 1.87-1.82 (m,1H), 1.60-1.56 (m, 1H), 1.44-1.40 (m, 1H).

Example 72(±)-trans-N-(8-amino-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 132)

Step 1:trans-N-(8-chloro-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of (3S)-3-hydroxypyrrolidin-2-one (216 mg, 2.14 mmol),trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(500 mg, 1.43 mmol), Pd₂(dba)₃ (128 mg, 0.14 mmol), xantphos (163 mg,0.28 mmol), and Cs₂CO₃ (929 mg, 2.86 mmol) in 1,4-dioxane (15 mL) wasstirred at 100° C. for 2 hours. The mixture was concentrated and theresidue was purified by flash column chromatography eluting with 0-20%MeOH in DCM to givetrans-N-[8-chloro-6-[(3S)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(90 mg, 17% yield) as a brown solid. LCMS (ESI): [M+H]⁺=371.1

Step 2:trans-N-(8-amino-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of Pd₂(dba)₃ (23 mg, 0.02 mmol), brettphos (26 mg, 0.05 mmol),t-BuONa (46 mg, 0.49 mmol), tert-butyl carbamate (284 mg, 2.43 mmol),and(trans-)-N-[8-chloro-6-[(3S)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(90 mg, 0.24 mmol) in 1,4-dioxane (8 mL) was stirred at 90° C. for 2hours. The mixture was concentrated and the residue was purified byflash column chromatography eluting with 0-100% ethyl acetate in PE togive tert-butylN-[3-[[(trans-)-2-cyanocyclopropanecarbonyl]amino]-6-[(3S)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-8-isoquinolyl]carbamate(52 mg, 47% yield) as a brown solid. LCMS (ESI): [M+H]⁺=452.0.

Step 3:trans-N-(8-amino-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of tert-butylN-[3-[[(trans+2-cyanocyclopropanecarbonyl]amino]-6-[(3S)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-8-isoquinolyl]carbamate(60 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (3 mL) andthe mixture was stirred at 25° C. for 2 hours. The mixture wasconcentrated and basified with NH₃ in methanol (7M), concentrated andpurified by reverse phase chromatography (acetonitrile 0-70/0.1% NH₄HCO₃in water) to affordtrans-N-[8-amino-6-[(3S)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(3 mg, 6.4% yield) as a brown solid. LCMS (ESI): R_(T) (min)=1.394,[M+H]⁺=352.1, method=C; ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.20(s, 1H), 8.14 (s, 1H), 7.28(d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H),6.33 (s, 2H), 5.79-5.78 (m, 1H), 4.34-4.28 (m, 1H), 3.79-3.71 (m, 1H),2.75-2.73 (m, 1H), 2.42-2.39 (m, 1H), 2.13-2.10(m, 1H), 1.87-1.82 (m,1H), 1.61-1.56 (m, 1H), 1.44-1.41 (m, 1H).

Example 73(±)-trans-N-[8-amino-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (Compound 133)

Step 1: 4-bromo-5-isopropyl-1-methyl-pyrazole

To a solution of 4-bromo-5-isopropyl-1H-pyrazole (950 mg, 5.03 mmol) inDMF (10 mL) was added sodium hydride (300 mg, 7.5 mmol) at 0° C. After10 min, iodomethane (0.5 mL, 7.4 mmol) was added. The reaction mixturewas stirred at 0° C. for 1 h, followed by the addition of 40 ml ofsaturated brine. The mixture was extracted with ethyl acetate (30 mL×3).The organics were washed with saturated brine (2 ×20 mL), then separatedand dried (Na₂SO₄). The organics were concentrated to afford crude4-bromo-5-isopropyl-1-methyl-pyrazole (900 mg) as a yellow liquid. LCMS(ESI): [M+H]⁺=203.1.

Step 2:8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (517 mg, 2.01 mmol),bis(pinacolato)diboron (600 mg, 2.36 mmol), Pd(dppf)Cl₂ (130 mg, 0.18mmol) and potassium acetate (500 mg, 5.09 mmol) in 1,4-dioxane (10 mL)was stirred under an Ar atmosphere at 90° C. for 2 h. The reaction wasconcentrated to dryness and purified by column chromatography (ethylacetate/petroleum ether 1/4 to 1/1) to afford8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine(600 mg, 89% yield) as a yellow solid. LCMS(ESI): [M+H]⁺=305.2.

Step 3:8-chloro-6-(5-isopropyl-1-methyl-pyrazol-4-yl)isoquinolin-3-amine

A mixture of 4-bromo-5-isopropyl-1-methyl-pyrazole (500 mg, 2.46 mmol),(3-amino-8-chloro-6-isoquinolyl) boronic acid (600 mg, 2.7 mmol),Pd(dppf)Cl₂ (140 mg, 0.19 mmol) and potassium carbonate (700 mg, 5.07mmol) was heated to 130° C. in a microwave reactor for 1 h. The reactionwas concentrated to dryness and purified by column chromatography (ethylacetate/petroleum ether1/3-1/2), followed by prep-HPLC to afford8-chloro-6-(5-isopropyl-1-methyl-pyrazol-4-yl) isoquinolin-3-amine (90mg, 12% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=301.1.

Step 4:(±)-trans-N-[8-chloro-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a mixture of (±)-trans-2-cyanocyclopropanecarboxylic acid (113 mg,1.02 mmol) and one drop of DMF in dichloromethane (10 mL) was addedoxalyl dichloride (0.3 mL, 3.52 mmol). The mixture was stirred at roomtemperature for 20 min. The mixture was concentrated to remove excessoxalyl dichloride and dichloromethane (5 mL) was then added. Thesolution was then added dropwise to a mixture of8-chloro-6-(5-isopropyl-1-methyl-pyrazol-4-yl)isoquinolin-3-amine (85mg, 0.28 mmol) and pyridine (0.5 mL, 6.18 mmol) in dichloromethane (5mL). The mixture was stirred at room temperature for 1 h. The reactionwas concentrated and purified by column chromatography (ethylacetate/dichloromethane=1/1) to afford(±)-trans-N-[8-chloro-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(110 mg , 97% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=394.2.

Step 5:(±)-trans-N-[8-(benzhydrylideneamino)-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A sealed tube containing(±)-trans-N-[8-chloro-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(110 mg, 0.28 mmol), benzophenone imine (225 mg, 1.24 mmol), Xantphos(70 mg, 0.12 mmol), Pd₂(dba)₃ (57 mg, 0.06 mmol) and Cs₂CO₃ (200 mg,0.62 mmol) in N,N-dimethylformamide (3 mL) and toluene (4 mL) wasstirred under an Ar atmosphere at 130° C. for 3 h. The reaction was thenquenched by the addition of 40 ml of brine and the mixture extractedwith ethyl acetate (30 mL×3). The organics were washed with brine (2×20mL) and concentrated. The residue was then purified by columnchromatography (ethyl acetate/petroleum ether 1/3-1/1) to affordtrans-N-[8-(benzhydrylideneamino)-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(64 mg, 27% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=539.3.

Step 6:(±)-trans-N-[8-amino-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A solution of(±)-trans-N-[8-(benzhydrylideneamino)-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(64mg, 0.08 mmol) and concentrated aqueous HCl (0.1 mL, 1.2 mmol) inmethyl alcohol (5 mL) was stirred at room temperature for 30min.Triethylamine (0.2 mL, 1.43 mmol) was then added. The reaction mixturewas then concentrated and purified by reverse phase chromatography(methanol 0-60/0.1% NH₄HCO₃ in water) to afford(±)-trans-N-[8-amino-6-(5-isopropyl-1-methyl-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(18 mg, 63% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=375.2,R_(T)(min)=1.72, Method=F; ¹HNMR (400 MHz,CD₃OD) δ 9.19 (s, 1H), 8.23(s, 1H), 7.45 (s, 1H), 6.96 (s, 1H), 6.73 (d, J=1.6 Hz, 1H), 3.95 (s,3H), 3.47-3.40 (m, 1H), 2.67-2.62(m, 1H), 2.15-2.10 (m, 1H), 1.62-1.52(m, 2H), 1.36 (d, J=6.8 Hz, 6H).

Example 74(±)-trans-N-[8-amino-6-(2-oxo-1,3-benzoxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 134)

Step 1:(±)-trans-N-[8-chloro-6-(2-hydroxyanilino)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(400 mg, 1.14 mmol), 2-aminophenol (150 mg, 1.37 mmol), Pd₂(dba)₃ (48mg, 0.05 mmol), Cs₂CO₃ (650 mg, 2 mmol), and Xantphos (60 mg, 0.1 mmol)in 1,4-dioxane (10 mL) was stirred under inert atmosphere at 100° C. for2 h. The reaction was concentrated undere reduced pressure. The residuewas then purified by column chromatography on silica gel eluting withethyl acetate/petroleum ether 1/5-1/1 to affordtrans-N-[8-chloro-6-(2-hydroxyanilino)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(420 mg, 78% yield) as yellow solid. LCMS(ESI):[M+H]⁺=379.1.

Step 2:(±)-trans-N-[8-chloro-6-(2-oxo-1,3-benzoxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A solution of(±)-trans-N-[8-chloro-6-(2-hydroxyanilino)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(400 mg, 1.06 mmol), 1,1′-carbonyldiimidazole (400 mg, 2.47 mmol),triethylamine (2.0 mL, 14.35 mmol) in dichloromethane (20 mL) wasstirred at room temperature for 2 h. The reaction was concentrated todryness and purified by silica gel column chromatography (ethylacetate/petroleum ether 1/3-1/1) to afford(±)-trans-N-[8-chloro-6-(2-oxo-1,3-benzoxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(260 mg, 52% yield) as a yellow solid. LCMS(ESI):[M+H]+=405.1.

Step 3: (±)-tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(2-oxo-1,3-benzoxazol-3-yl)-8-isoquinolyl]carbamate

A mixture of(±)-trans-N-[8-chloro-6-(2-oxo-1,3-benzoxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 0.49 mmol), tert-butyl carbamate (600 mg, 5.12 mmol), Brettphos(120 mg, 0.22 mmol), Pd₂(dba)₃ (100 mg, 0.11 mmol) and Cs₂CO₃ (325 mg, 1mmol) in 1,4-dioxane (10 mL) was stirred under an Ar atmosphere at 90°C. for 2 h. The reaction was concentrated to dryness and purified bysilica gel column chromatography eluting with ethyl acetate/petroleumether (1/1) to afford (±)-tert-butyl N-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(2-oxo-1,3-benzoxazol-3-yl)-8-isoquinolyl]carbamate(62 mg, 21% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=486.1.

Step 4:(±)-trans-N-[8-amino-6-(2-oxo-1,3-benzoxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A solution of (±)-tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(2-oxo-1,3-benzoxazol-3-yl)-8-isoquinolyl]carbamate(62 mg, 0.13 mmol) in methyl alcohol (2 mL) and HCl (4 M in dioxane, 2mL, 8 mmol) was stirred at room temperature for 1 h.The reaction wasquenched by adding NaHCO₃ powder and purified by prep-HPLC to afford(±)-trans-N-[8-amino-6-(2-oxo-1,3-benzoxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (6 mg, 11.8% yield) as a red solid. LCMS(ESI):[M+H]+=386.1,RT(min)=1.83 method=B; ¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.38(s, 1H), 8.28 (s, 1H), 7.46 (s, 1H), 7.25-7.22 (m, 3H), 7.16 (s, 1H),6.82 (d, J=1.2 Hz, 1H), 6.65-6.64 (m, 2H), 2.78-2.76 (m, 1H), 2.17-2.12(m, 1H), 1.62-1.58 (m, 1H), 1.46-1.41(m, 1H).

Example 751-[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(Compound 135)

Step 1: 1-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-3-methyl-urea

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (400 mg, 1.24mmol) in tetrahydrofuran (5 mL) was added in triethylamine (4 mL, 28.7mmol) and triphosgene (400 mg, 1.35 mmol). The mixture was stirred atroom temperature for 10 min prior to the addition of methanaminehydrochloride (940 mg, 13.92 mmol). The reaction mixture was stirred atroom temperature for 1 h. The mixture was concentrated to dryness andpurified by column chromatography eluting ethyl acetate/petroleum ether(1/3-1/1) to afford1-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-3-methyl-urea (190 mg, 33%yield) as a yellow solid. LCMS (ESI): [M+H]⁺=379.9.

Step 2:1-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea

A mixture of 1-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-3-methyl-urea(190 mg, 0.50 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120mg, 0.55 mmol), Pd(dppf)Cl₂ (40 mg, 0.05 mmol), and K₂CO₃ (180 mg, 1.3mmol) in 1,4-dioxane (6 mL) and water (1 mL) was stirred under an Aratmosphere at 80° C. for 3 h. The reaction mixture was concentrated todryness and the crude was then purified by column chromatography elutingmethanol/dichloromethane (1:12) to afford1-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(145 mg, 74% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=345.0.

Step 3: tert-butylN-[7-fluoro-3-(methylcarbamoylamino)-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate

A mixture of1-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(120 mg, 0.35 mmol), tert-butyl carbamate (515 mg, 4.4 mmol), Pd₂(dba)₃(70 mg, 0.08 mmol), Brettphos (90 mg, 0.17 mmol) and Cs₂CO₃ (260 mg,0.80 mmol) in 1,4-dioxane (6 mL) was stirred under an Ar atmosphere at90° C. for 1 h. The reaction was purified by reverse phasechromatography (methanol 0-50/0.1% ammonia in water) to affordtert-butylN-[7-fluoro-3-(methylcarbamoylamino)-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate (30 mg, 18% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=426.2.

Step4:1-[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea

A solution of tert-butylN-[7-fluoro-3-(methylcarbamoylamino)-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate (30 mg, 0.07 mmol) in a HCl in dioxane solution (4 M, 2 mL, 8mmol) was stirred at room temperature for 2 h. The solution wasconcentrated and purified by reverse phase chromatography (methanol5-50/0.05% ammonia in water) to afford1-[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(15.4 mg, 67% yield) as a yellow solid. LCMS(ESI):[M+H]⁺=326.1,R_(T)(min)=1.40, Method=E; ¹H NMR (400 MHz, CD₃OD) δ 9.25 (s, 1H), 8.47(d, J=5.6 Hz, 1H), 8.41 (s, 1H), 7.53 (s, 1H), 7.40 (d, J=5.2 Hz, 1H),6.91 (d, J=6.0 Hz, 1H), 2.91 (s, 3H), 2.31 (s, 3H).

Example 76(±)-trans-3-(8-amino-3-(2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-N,4-dimethylbenzamide(Compound 136)

Step 1: 3-bromo-N,4-dimethylbenzamide

To a vial was added 4-bromo-3-methylbenzoic acid (1 g, 4. mmol),dichloromethane (10 mL), DMF (0.1 mL, 4. mmol) and oxalyl chloride (1.2mL, 14.18 mmol). The mixture was stirred at rt for 2 h. The mixture wasthen concentrated in vacuo. The mixture was re-dissolved indichloromethane (10 mL) and methanamine (30% in EtOH, 10 mL) was added.The mixture was stirred at rt. for 30 min. The mixture was concentratedin vacuo and purified by column chromatography (PE/EA from 1:1 to 0:100)to get 4-bromo-N,3-dimethyl-benzamide (820 mg, 77% yield) as a whitesolid. LCMS (ESI) [M+H]⁺=228.1.

Step 2:N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a sealed tube was added 3-bromo-N,4-dimethyl-benzamide (800 mg, 3.51mmol), bis(pinacolato)diboron (1.1 g, 4.33 mmol), acetoxypotassium (1.1g, 11.21 mmol) and Pd(dppf)Cl₂ (256 mg, 0.35 mmol) and 1,4-dioxane (100mL). The mixture was bubbled with N₂ for 2 min, and then stirred at 100°C. for 3 h. The mixture was purified directly by silica-gel columnchromatography (EA:PE=1:3 to 1:2) to giveN,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(800 mg, 41% yield) as a white solid. LCMS (ESI) [M+H]⁺=276.1.

Step 3:(±)-trans-3-(8-chloro-3-(2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-N,4-dimethylbenzamide

A solution of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(200 mg, 0.57 mmol),N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(500 mg, 0.91 mmol), Pd(dppf)Cl₂ (50 mg, 0.07 mmol), and Na₂CO₃ (130 mg,1.24 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was heated at 90° C.for 2 h under Ar. The mixture was purified directly by silica-gel columnchormatography (EA:PE=1:2 to 1:1) to give(±)-trans-3-[8-chloro-3-[(2-cyanocyclopropane carbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-benzamide (200 mg, 84% yield) as awhite solid. LCMS (ESI) [M+H]⁺=419.1.

Step 4:(±)-trans-3-(8-amino-3-(2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-N,4-dimethylbenzamide

A mixture of(±)-trans-3-[8-chloro-3-[(2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-benzamide(100 mg, 0.24 mmol), tert-butyl carbamate (265 mg, 2.26 mmol), Xantphos(55 mg, 0.10 mmol), Pd₂(dba)₃ (44 mg, 0.05 mmol) and Cs₂CO₃ (350 mg,1.08 mmol) in dry N,N-dimethylformamide (5 mL) and dry toluene (5 mL)was stirred at 130 ° C. under Ar for 16 h. The reaction was concentratedto remove toluene and then 20 mL saturated brine solution was added. Themixture was extracted with ethyl acetate (20 mL×2). The organics werethen separated and dried (Na₂SO₄). The resulting residue was purified bysilica-gel column chromatography (EA:PE=1:1 to EA to DCM:MeOH=20:1)followed by reverse phase chromatography (acetonitrile 0-50/0.1% NH₄HCO₃in water) to afford(±)-trans-3-[8-amino-3-[(2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]-N,4-dimethyl-benzamide(29 mg, 31% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.67,[M+H]⁺=400.1, method=C; ¹H NMR (400 MHz, CD₃OD): δ 9.24 (s, 1H), 8.27(s, 1H), 7.75-7.73 (m, 2H), 7.40-7.38 (m, 1H), 6.97 (s, 1H), 6.71 (s,1H), 2.92 (s, 3H), 2.67-2.62 (m, 1H), 2.34 (s, 3H), 2.14-2.09 (m, 1H),1.62-1.52 (m, 2H).

Example 77(±)-trans-N-(8-amino-6-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 138)

Step 1:(±)-trans-N-(8-chloro-6-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(200 mg, 0.57 mmol), 1-methyl-2-benzimidazolinone (120 mg, 0.81 mmol),Pd₃(dba)₂ (100 mg, 0.11 mmol), Xantphos (130 mg, 0.22 mmol) and K₃PO₄(360 mg, 1.7 mmol) in 1,4-dioxane (15 mL) was heated at 90° C. for 3 hunder Ar. The mixture was concentrated and purified by silica-gel columnchromatography (EA:PE=1:3 to 1:2) to give(±)-trans-N-[8-chloro-6-(3-methyl-2-oxo-benzimidazol-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(120 mg, 50% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=418.1.

Step 2: (±)-tert-butyl3-(trans-2-cyanocyclopropanecarboxamido)-6-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-8-ylcarbamate

A mixture of(±)-trans-N-[8-chloro-6-(3-methyl-2-oxo-benzimidazol-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.24 mmol), tert-butyl carbamate (280 mg, 2.39 mmol), Pd₃(dba)₂(40 mg, 0.04 mmol), Brettphos (20 mg, 0.04 mmol), Cs₂CO₃ (230 mg, 0.71mmol) in 1,4-dioxane (1 mL) was heated at 90° C. for 3 h under Ar. Themixture was directly purified by silica gel column chormatography(EA:PE=1:2) to give (±)-tert-butylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-(3-methyl-2-oxo-benzimidazol-1-yl)-8-isoquinolyl]carbamate(70 mg, 59% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=499.1.

Step 3:(±)-trans-N-(8-amino-6-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To the (±)-tert-butylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-(3-methyl-2-oxo-benzimidazol-1-yl)-8-isoquinolyl]carbamate(60 mg, 0.12 mmol) dissolved in dichloromethane (4 mL) was added TFA(0.2 mL, 0.24 mmol) and stirred at room temperture for 2 h. The mixturewas directly purified by reverse phase chromatography (acetonitrile0-50/0.1% NH₄HCO₃ in water) to afford(±)-trans-N-[8-amino-6-(3-methyl-2-oxo-benzimidazol-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(13 mg, 27% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.77,[M+H]⁺=399.1, method=C; ¹H NMR (400 MHz, DMSO-d₆): δ 11.15 (s, 1H), 9.35(s, 1H), 8.26 (s, 1H), 7.27-7.08 (m, 5H), 6.78 (s, 1H), 6.54 (s, 2H),3.17 (s, 3H), 2.77-2.74 (m, 1H), 2.17-2.12 (m, 1H), 1.62-1.57 (m, 1H),1.46-1.41 (m, 1H).

Example 78(±)-trans-N-(8-amino-6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 139)

Step 1:(±)-trans-N-(8-chloro-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A solution of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(200 mg, 0.57 mmol),1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(320 mg, 1.15 mmol), Pd(dppf)Cl₂ (50 mg, 0.07 mmol) and Na₂CO₃ (130 mg,1.24 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was heated at 90° C.for 2 h under Ar. The mixture was directly purified by silica gel columnchromatography (EA:PE=1:2) to give(±)-trans-N-[8-chloro-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(220 mg, 91% yield) as a white solid. LCMS (ESI) [M+H]⁺=422.7.

Step 2:(±)-trans-N-(8-amino-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-[8-chloro-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(200 mg, 0.47 mmol), tert-butyl carbamate (555 mg, 4.74 mmol), Xantphos(110 mg, 0.19 mmol), Pd₂(dba)₃ (90 mg, 0.10 mmol) and Cs₂CO₃ (690 mg,2.12 mmol) in dry N,N-dimethylformamide (5 mL) and toluene (5 mL) wasstirred at 130° C. under Ar atmosphere for 4 h. The reaction wasconcentrated to remove toluene and then a 10 mL saturated brine solutionwas added. The mixture was extracted with ethyl acetate (10 mL×2). Theorganics were then separated and dried (Na₂SO₄). The resulting residuewas purified by silica gel column chromatography (EA:PE=1:1 to 2:1) togive(±)-trans-N-[8-amino-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 52% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=403.7.

Step 3:(±)-trans-N-(8-amino-6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

The(±)-trans-N-[8-amino-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(80 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL), and addedthe TFA (1.5 mL, 0.20 mmol) stirred at room temperture for 2 h. Themixture was evaporated and neutralized by adding a solution of NH₃ inMeOH. The resulting mixture was purified by reverse phase chromatography(acetonitrile 0-50/0.1% NH₄HCO₃ in water) to afford(±)-trans-N-[8-amino-6-(1H-pyrazol-4-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(26 mg, 42% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.47,[M+H]⁺=319.7, Method=C; ¹HNMR (400 MHz, DMSO-d₆): δ 13.01 (s, 1H), 11.02(s, 1H), 9.21 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.19(s, 1H), 6.86 (s, 1H), 6.17 (s, 2H), 2.77-2.74 (m, 1H), 2.15-2.11 (m,1H), 1.61-1.56 (m, 1H), 1.46-1.41 (m, 1H).

Example 79(±)-trans-N-(8-amino-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 140)

Step 1:(±)-trans-N-(8-chloro-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(200 mg, 0.57 mmol), 2-hydroxybenzimidazole (110 mg, 0.82 mmol),Pd₂(dba)₃ (100 mg, 0.11 mmol), Xanphos (130 mg, 0.22 mmol), K₃PO₄ (360mg, 1.70 mmol) in 1,4-dioxane (15 mL) was heated at 90° C. for 3 h underAr gas. The mixture was directly purified by silica gel columnchromatography (EA:PE=1:1) to give(±)-trans-N-[8-chloro-6-(2-oxo-3H-benzimidazol-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(180 mg, 78% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=404.1.

Step 2: (±)-tert-butyl3-(trans-2-cyanocyclopropanecarboxamido)-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-8-ylcarbamate

A mixture of(±)-trans-N-[8-chloro-6-(2-oxo-3H-benzimidazol-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(160 mg, 0.40 mmol), tert-butyl carbamate (696 mg, 5.94 mmol), Pd₂(dba)₃(72 mg, 0.08 mmol), Brettphos (40 mg, 0.07 mmol) and Cs₂CO₃ (387 mg,1.19 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 3 h under Ar.The reaction was concentrated to dryness. The residue was purified withsilica chromatography (PE:EA=2:1 to PE:EA=1:1) to give (±)-tert-butylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-(2-oxo-3H-benzimidazol-1-yl)-8-isoquinolyl]carbamate(60 mg, 31% yield) as a white solid. LCMS (ESI) [M+H]⁺=485.1.

Step 3:(±)-trans-N-(8-amino-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of (±)-tert-ButylN-[3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-(2-oxo-3H-benzimidazol-1-yl)-8-isoquinolyl]carbamate(55 mg, 0.11 mmol) dissolved in dichloromethane (2 mL) was added TFA(1.0 mL, 0.11 mmol). The reaction was stirred at room temperture for 2h. The mixture was directly purified by silica gel column chromatography(EA:PE=1:1 to EA), followed by reverse phase chromatography(acetonitrile 0-50/0.1% NH₄HCO₃ in water) to afford(±)-trans-N-[8-amino-6-(2-oxo-3H-benzimidazol-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(2.6 mg, 6% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.64,[M+H]⁺=385.1, method=C; ¹HNMR (400 MHz, DMSO-d₆): δ 11.13 (s, 1H), 9.34(s, 1H), 8.25 (s, 1H), 7.15-7.00 (m, 6H), 6.79 (s, 1H), 6.51 (s, 2H),2.78-2.74 (m, 1H), 2.17-2.12 (m, 1H), 1.61-1.57 (m, 1H), 1.46-1.41 (m,1H).

Example 80(±)-trans-N-(8-amino-6-(4-methylpyridin-3-yl)-7-(trifluoromethyl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 143)

Step 1:(±)-trans-N-(8-chloro-7-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A solution of(±)-trans-N-[7-bromo-8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(500 mg, 1.13 mmol), iodosodium (750 mg, 5 mmol), CuI (50 mg, 0.26 mmol)and dimethylethane-1,2-diamine (1.5 mL, 13.69 mmol) in 1,4-dioxane (20mL) was heated to 110° C. for 2 days. The mixture was diluted with ethylacetate (100 mL), washed with water (30 mL×3) and brine (30 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by silica gel column (EA:PE=1:1) togive(±)-trans-N-[8-chloro-7-iodo-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(430 mg, 78% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=489.0.

Step 2:(±)-(trans)-N-(8-chloro-6-(4-methylpyridin-3-yl)-7-(trifluoromethyl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of(±)-(trans)-N-[8-chloro-7-iodo-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(370 mg, 0.76 mmol) and diphenyl(trifluoromethyl)sulfoniumtrifluoromethanesulfonate (620 mg, 1.53 mmol) in N,N-dimethylformamide(11 mL) was added Cu (150 mg, 2.34 mmol) at room temperature. Themixture was heated to 67° C. for 16 h. After cooling, the reactionmixture was dissolved in EtOAc (30 mL), washed with saturated aqueoussodium chloride (10 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EA:PE=2:3) followed by reverse phasechromatography (acetonitrile 0-40/0.1% HCOOH in water) to afford(±)-(trans)-N-[8-chloro-6-(4-methyl-3-pyridyl)-7-(trifluoromethyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(35 mg, 11% yield). LCMS (ESI) [M+H]⁺=431.1.

Step 3:(±)-(trans)-2-cyano-N-(8-(diphenylmethyleneamino)-6-(4-methylpyridin-3-yl)-7-(trifluoromethyl)isoquinolin-3-yl)cyclopropanecarboxamide

A mixture of(±)-(trans)-N-[8-chloro-6-(4-methyl-3-pyridyl)-7-(trifluoromethyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(30 mg, 0.07 mmol), Pd₂(dba)₃ (12 mg, 0.01 mmol), Xantphos (15 mg, 0.03mmol), Cs₂CO₃ (48 mg, 0.15 mmol), and benzophenone imine (300 mg, 1.66mmol) in 1,4-dioxane (5 mL) was stirred at 115° C. under Ar for 6 h. Thereaction was directly purified by silica gel column (EA:PE=1:5 to 1:1)to give(±)-(trans)-N-[8-(benzhydrylideneamino)-6-(4-methyl-3-pyridyl)-7-(trifluoromethyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(20 mg, 50% yield) as a yellow oil. LCMS (ESI) [M+H]⁺=576.2.

Step 4:(±)-(trans)-N-(8-amino-6-(4-methylpyridin-3-yl)-7-(trifluoromethyl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A solution of(±)-(trans)-N-[8-(benzhydrylideneamino)-6-(4-methyl-3-pyridyl)-7-(trifluoromethyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(20 mg, 0.02 mmol) in acetonitrile (1 mL), water (1 mL) and2,2,2-trifluoroacetic acid (0.5 mL) was stirred for 2 h. Then 0.2 mLconcentrated HCl was added and the mixture stirred for 16 h. The mixturewas evaporated, dissolved in CH₃CN (1 mL), and neutralized with sat.sodium bicarbonate. The resulting mixture was purified by reverse phasechromatography (acetonitrile 17-47/0.05% ammonia in water) to give(±)-(trans)-N-[8-amino-6-(4-methyl-3-pyridyl)-7-(trifluoromethyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(4 mg, 40% yield) as a white solid. LCMS (ESI) R_(T) (min)=1.864,[M+H]⁺=421.1, Method=C; ¹HNMR (400 MHz, CD₃OD): δ 9.41 (s, 1H), 8.39 (s,1H), 8.25-8.23 (m, 2H), 7.35 (s, 1H), 6.74 (s, 1H), 2.64-2.26 (m, 1H),2.16 (s, 3H), 2.09-2.05 (m, 1H), 1.57-1.47 (m, 2H).

Example 81(±)-(trans)-N-(8-amino-6-(5-methyl-2-oxoimidazolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 144)

Step 1: tert-butyl8-chloro-3-((trans)-2-cyanocyclopropanecarboxamido)isoquinolin-6-ylcarbamate

A mixture of(trans)-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(600 mg, 1.71 mmol), Pd₂(dba)₃ (240 mg, 0.26 mmol), Xantphos (300 mg,0.52 mmol), K₂CO₃ (510 mg, 3.7 mmol) and tert-butyl carbamate (400 mg,3.41 mmol) in 1,4-dioxane (20 mL) under Ar was stirred at 90° C. for 7h. The mixture was directly purified by silica gel column (EA:PE=1:5 to1:3) to give tert-butylN-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]carbamate(500 mg, 76% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=387.1.

Step 2:(trans)-N-(8-chloro-6-(5-methyl-2-oxoimidazolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a stirred solution of tert-butylN-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]carbamate(450 mg, 1.16 mmol) in N,N-dimethylformamide (20 mL) was added NaH (450mg, 11.25 mmol) at 0° C. The resulting mixture was stirred for 30 min at0° C. Then tert-butyl N-(2-bromopropyl)carbamate (500 mg, 2.1 mmol) wasadded. The resulting mixture was stirred overnight at 80° C. Aftercooling to room temperature, the mixture was quenched with sat. NH₄Cl,and diluted with ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column (EA:PE=1:1) to givetert-butylN-[2-[[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]amino]propyl]carbamate(25 mg, 5% yield) as a light yellow solid. LCMS (ESI) [M+H]⁺=370.1.

Step 3: tert-butyl3-((trans)-2-cyanocyclopropanecarboxamido)-6-(5-methyl-2-oxoimidazolidin-1-yl)isoquinolin-8-ylcarbamate

A mixture of(trans)-N-[8-chloro-6-(5-methyl-2-oxo-imidazolidin-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(25 mg, 0.07 mmol), tert-butyl carbamate (80 mg, 0.68 mmol), Pd₂(dba)₃(12 mg, 0.01 mmol), Brettphos (12 mg, 0.02 mmol) and Cs₂CO₃ (65 mg, 0.20mmol) in 1,4-dioxane (2 mL) was heated at 90° C. for 3 h under Ar. Themixture was directly purified by silica gel column (EA:PE=1:1 to 100%EA) to give tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(5-methyl-2-oxo-imidazolidin-1-yl)-8-isoquinolyl]carbamate(15 mg, 49% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=451.1.

Step 4:(trans)-N-(8-amino-6-(5-methyl-2-oxoimidazolidin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A solution of tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(5-methyl-2-oxo-imidazolidin-1-yl)-8-isoquinolyl]carbamate(15 mg, 0.03 mmol) in dichloromethane (4 mL) and 2,2,2-trifluoroaceticacid (1 mL) was stirred for 30 min at room temperature. The mixture wasevaporated and purified by reverse phase chromatography (acetonitrile17-47/0.05% HCOOH in water) to give(trans)-N-[8-amino-6-(5-methyl-2-oxo-imidazolidin-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(3 mg, 26% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.332,[M+H]⁺=351.2, Method=A; ¹HNMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 9.11(s, 1H), 8.08 (s, 1H), 7.36 (s, 1H), 7.25 (s, 1H), 6.71(s, 1H), 6.18 (s,2H), 4.12-3.97 (m, 2H), 3.81-3.75 (m, 1H), 2.76-2.67 (m, 1H), 2.14-2.08(m, 1H), 1.58-1.50 (m, 1H), 1.42-1.40 (m, 1H), 1.20 (d, J=6.0 Hz, 3H).

Example 82(±)-trans-N-(8-amino-5,7-difluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 145)

To a solution of(±)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (100 mg, 0.29 mmol) in acetonitrile (5 mL) was added1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)(220 mg, 0.69 mmol). The mixture was stirred at 90° C. for 2 h in amicrowave reactor. The crude was purified by prep-HPLC (Column Xbridge21.2×250 mm c18, 10 um Mobile Phase A: water (10 mMol/LNH₄HCO₃) B: ACN)to give(±)-trans-N-[8-amino-5,7-difluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(5 mg, 4.5% yield). (ESI): R_(T) (min)=1.625, [M+H]⁺=380.2, method=G; 1HNMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 9.53 (s, 1H), 8.55 (d, J=5.2 Hz,1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.48 (d, J=5.2 Hz, 1H), 6.20 (s, 2H),2.62-2.75 (m, 1H), 2.11-2.25 (m, 4H), 1.60-1.68 (m, 1H),1.40-1.48 (m,1H).

Example 83(±)-trans-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 146)

Step 1:trans-2-cyano-N-(8-(diphenylmethyleneamino)-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

To a sealed tube was added(±)-trans-N-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(450 mg, 1.24 mmol), Xantphos (300 mg, 0.52 mmol), Pd₂(dba)₃ (225 mg,0.25 mmol), Cs₂CO₃ (1.0 g, 3.08 mmol), benzophenone imine (1.2 g, 6.62mmol), and N,N-dimethylformamide (15 mL). The mixture was bubbled withN₂ for 2 min, stirred at 130° C. for 4 hours. The mixture wasconcentrated and purified by silica-gel column chromatography (elutedwith PE/EA from 10:1 to 1:1) to get(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(250 mg, 31% yield) as yellow solid. LCMS (ESI) [M+H]⁺=508.3.

Step 2:(±)-trans-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a vial was added(±)-trans-N-[8-(benzhydrylideneamino)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(500 mg, 0.39 mmol), tetrahydrofuran (5 mL), and 2 N HCl (4.81 mL, 9.63mmol). The mixture was stirred at rt for 2 hours. The mixture wasconcentrated and purified by silica-gel column chromatography (withDCM/MeOH from 20:1 to 10:1) followed by prep-HPLC (Mobile Phase: A:Water (10 mmol NH₄HCO₃) B: Acetonitrile) to give(±)-trans-N-[8-amino-7-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(11 mg, 8% yield) as a pale-brown solid. LCMS (ESI): R_(T) (min)=1.667,[M+H]⁺=378.1, Method=G; ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.48(d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.36 (d, J=5.2 Hz, 1H),6.96 (s, 1H), 6.61 (s, 1H), 6.03 (br, 2H), 2.79-2.71 (m, 1H), 2.17-2.10(m, 1H), 2.11 (s, 3H), 1.63-1.55 (m, 1H), 1.46-1.40 (m, 1H).

Example 841-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea(Compound 147) and1-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea(Compound 148)

Step 1:1-(8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea

To a sealed tube was added8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (700 mg, 2.6 mmol),methylaminoformylchloride (1.2 g, 13 mmol), DBU (1 mL, 6.69 mmol) and1,4-dioxane (10 mL). The reaction was stirred at 120° C. for 16 h. Themixture was concentrated and purified by silica-gel columnchromatography (eluted with DCM/MeOH from 100:1 to 30:1) to give1-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea (820 mg,84% yield) as a brown solid. LCMS (ESI): [M+H]⁺=327.1.

Step 2: tert-butyl6-(4-methylpyridin-3-yl)-3-(3-methylureido)isoquinolin-8-ylcarbamate

To a reaction vial was added1-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea (800 mg,2.45 mmol), Brettphos (200 mg, 0.37 mmol), Pd₂(dba)₃ (300 mg, 0.33mmol), Cs₂CO₃ (2.0 g, 6.15 mmol) , tert-butyl carbamate (1.6 g, 13.7mmol) and 1,4-dioxane (50 mL), bubbled with N₂ for 2 min. The reactionwas stirred at 95° C. for 3 hours. The mixture was concentrated andpurified by silica-gel column chromatography (eluted with DCM/MeOH from100:1 to 30:1) to get tert-butylN-[3-(methylcarbamoylamino)-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(430 mg, 41% yield) as a brown solid. LCMS (ESI): [M+H]⁺=408.1.

Step 3:1-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea

To a reaction vial was added tert-butylN-[3-(methylcarbamoylamino)-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(420 mg, 0.98 mmol) and HCl (4 N in dioxane, 5 mL). The reaction wasstirred at rt for 4 hours. The mixture was concentrated and re-dissolvedin a solution of NH₃ in MeOH (7 N, 20 mL) The mixture was concentratedand purified by silica-gel column chromatography (eluted with DCM/MeOHfrom 30:1 to 10:1) to get1-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea (230 mg,75% yield) as yellow solid. LCMS (ESI): [M+H]⁺=308.2.

Step 4:1-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylureaand1-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea

To a vial was added1-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea (100 mg,0.33 mmol), acetonitrile (10 mL) and N-chlorosuccinimide (45 mg, 0.34mmol). The mixture was stirred at 50° C. for 16 hours. The mixture wasconcentrated and purified by prep-HPLC (acetonitrile 30-70%/0.1% NH₄OHin water) to provide the following:1-[8-amino-7-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(Compound 147) as a yellow solid (38 mg, 34% yield). LCMS (ESI): R_(T)(min)=1.533, [M+H]⁺=342.2, method=G; ¹H NMR (400 MHz, DMSO-d₆) δ 9.35(s, 1H), 9.12 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 7.82 (s,1H), 7.36 (d, J=5.2 Hz, 1H), 7.04 (q, J=4.8 Hz, 1H), 6.85 (s, 1H), 6.52(s, 2H), 2.71 (d, J=4.8 Hz, 3H), 2.12 (s, 3H).1-[8-amino-5-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(Compound 148) as a yellow solid (21 mg, 19% yield). LCMS (ESI): R_(T)(min)=1.499, [M+H]⁺=342.1, method=G; ¹H NMR (400 MHz, DMSO-d6) δ 9.28(s, 1H), 9.23 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.22 (s,1H), 7.37 (d, J=5.2 Hz, 1H), 7.06 (q, J=4.8 Hz, 1H), 6.49 (s, 2H), 6.36(s, 1H), 2.72 (d, J=4.8 Hz, 3H), 2.12 (s, 3H).

Example 851-(8-amino-5-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea(Compound149)1-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea(Compound 150)

Step 1:1-(8-amino-5-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylureaand1-(8-amino-7-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea

To a reaction vial was added1-[8-amino-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea (100 mg,0.33 mmol), acetic acid (5 mL) and N-iodosuccinimide (75 mg, 0.33 mmol).The mixture was stirred at 20° C. for 3 days. The mixture wasconcentrated and pH adjusted to 7 with sat. NaHCO₃. The productextracted with ethyl acetate (50 mL×2), dried over Na₂SO₄, filtered andconcentrated to give a crude mixture of1-(8-amino-5-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylureaand1-(8-amino-7-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea.The crude mixture was used in the next step without furtherpurification. LCMS (ESI): [M+H]+=434.1

Step 2:1-(8-amino-5-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea&1-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea

To a vial was added a mixture of1-(8-amino-5-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea&1-(8-amino-7-iodo-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylurea(100 mg, 0.23 mmol), Pd(t-Bu₃P)₂ (15 mg, 0.03 mmol), Zn (5 mg, 0.08mmol), Zn(CN)₂ (50 mg, 0.43 mmol) and N,N-dimethylformamide (5 mL). Thereaction mixture was bubbled for 2 min with N₂ and stirred at 90° C. for4 hours. The mixture was concentrated and purified by silica-gel columnchromatography (eluted with DCM/MeOH from 100:1 to30:1) to give:Compound 149:1-[8-amino-7-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(14 mg, 18% yield) as a white solid. LCMS (ESI): RT (min)=1.512,[M+H]⁺=333.1, method=C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 9.32(s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.39 (d,J=5.2 Hz, 1H), 7.35 (s, 2H), 7.07 (q, J=4.4 Hz, 1H), 6.80 (s, 1H), 2.71(d, J=4.4 Hz, 3H), 2.22 (s, 3H). Compound 150:1-[8-amino-5-cyano-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea(23 mg, 30% yield) was isolated as a white solid. LCMS (ESI): RT(min)=1.428, [M+H]⁺=333.2, method=G; ¹H NMR (400 MHz, DMSO-d₆) δ 9.37(s, 1H), 9.34 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.43 (s, 1H), 8.18 (s,1H), 7.50 (s, 2H), 7.43 (d, J=5.2 Hz, 1H), 7.00 (q, J=4.4 Hz, 1H), 6.41(s, 1H), 2.73 (d, J=4.4 Hz, 3H), 2.22 (s, 3H).

Example 86(±)-trans-N-[8-amino-6-(2-oxooxazolidin-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 151)

Step 1: tert-butylN-[2-(3-amino-8-chloro-6-isoquinolyl)-2-oxo-ethyl]carbamate

To a solution of 6-bromo-8-chloro-isoquinolin-3-amine (500 mg, 1.94mmol) in dry tetrahydrofuran (20 mL) was added iPrMgCl.LiCl complex (1.3M in THF) (20 mL, 26 mmol) at 0° C. under N₂. After addition completed,the reaction solution was stirred at rt for 1 h. The mixture was cooledto 0° C. and added (±)-tert-butyl2-(methoxy(methyl)amino)-2-oxoethylcarbamate (1.27 g, 5.83 mmol). Thereaction solution was stirred at rt for 1 h. The reaction mixture wasquenched by the addition of the saturated aqueous NaCl and extractedwith ethyl acetate (30 mL×3). The organic extract was dried withanhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by flash column chromatography eluting with 40% ethyl acetatein PE to give tert-butylN-[2-(3-amino-8-chloro-6-isoquinolyl)-2-oxo-ethyl]carbamate (330 mg, 48%yield) as a yellow oil. LCMS (ESI): [M+H]⁺=336.1.

Step 2: tert-butylN-[2-(3-amino-8-chloro-6-isoquinolyl)-2-hydroxy-ethyl]carbamate

To a solution of tert-butylN-[2-(3-amino-8-chloro-6-isoquinolyl)-2-oxo-ethyl]carbamate (150 mg,0.45 mmol) in MeOH (3 mL) was added NaBH₄ (42 mg, 1.12 mmol) at 0° C.The resulting solution was stirred at 0° C. for 1 h. The water (5 mL)was added to quenched the reaction. The mixture was extracted by EA (10mL×2). The organic layers were washed with water (5 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude producttert-butylN-[2-(3-amino-8-chloro-6-isoquinolyl)-2-hydroxy-ethyl]carbamate (140 mg,93% yield) was used in the next step without purification. LCMS (ESI):[M+H-100]⁺=338.1.

Step 3: 5-(3-amino-8-chloro-6-isoquinolyl)oxazolidin-2-one

The tert-butylN-[2-(3-amino-8-chloro-6-isoquinolyl)-2-hydroxy-ethyl]carbamate (140 mg,0.41 mmol) was dissolved in N,N-dimethylformamide (3 mL). NaH (15mg,0.62 mmol) was added at 0° C. The resulting solution was stirred at roomtemperature for 3 h. Water (5 mL) was added to quench the reaction andthe mixture was extracted with ethyl acetate (10 mL×2). The organiclayers were washed with brine (10 mL×3), dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified by prep-TLC(DCM:MeOH=20:1) to obtained the title product5-(3-amino-8-chloro-6-isoquinolyl)oxazolidin-2-one (60 mg, 51% yield) asa yellow oil. LCMS (ESI): [M+H]⁺=264.0.

Step 4:trans-N-[8-chloro-6-(2-oxooxazolidin-5-yl)-3-isoquinolyl]-2-cyano-cyclopropaneCarboxamide

A mixture of (±)-trans-2-cyanocyclopropanecarboxylic acid (250 mg, 2.25mmol) in dichloromethane (5 mL) was stirred at 0° C. for 10 min. Thenethanedioyl dichloride (572 mg, 4.51 mmol) was added dropwise. Thereaction mixture was stirred at 25° C. for 1 h, and concentrated. Thecrude product was then added to a solution of5-(3-amino-8-chloro-6-isoquinolyl)oxazolidin-2-one (60 mg, 0.23 mmol)and pyridine (0.06 mL, 0.68 mmol) in dichloromethane (5 mL) at 0° C. Thereaction mixture was stirred at 25° C. for 1 h. The reaction mixture wasfiltered and concentrated. The residue was purified by flash columnchromatography (DCM/MeOH=10/1) to givetrans-N-[8-chloro-6-(2-oxooxazolidin-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(70 mg, 86% yield) as a white solid. LCMS (ESI): [M+H]⁺=357.0.

Step 5:trans-N-[8-amino-6-(2-oxooxazolidin-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a sealed tube was added tert-butyl carbamate (229 mg, 1.96 mmol),Pd₂(dba)₃(36 mg, 0.04 mmol), Cs₂CO₃(192 mg, 0.59 mmol), xantphos (38 mg,0.08 mmol),trans-N-[8-chloro-6-(2-oxooxazolidin-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(70 mg, 0.20 mmol), N,N-dimethylformamide (1 mL) and toluene (1 mL) inglove box. The mixture was stirred at 130° C. for 2 d. The reaction wasconcentrated and diluted with water (20 mL). The mixture was extractedwith ethyl acetate (30 mL×3) and the combined organic layers was washedwith water (20 mL), saturated NaCl solution (30 mL×3), dried over sodiumsulfate, filtered and concentrated. The crude product was purified byprep-HPLC (mobile phase:A water (0.01% NH₃)+10 mm (NH₄HCO₃), BAcetonitrile) to givetrans-N-[8-amino-6-(2-oxooxazolidin-5-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(4.8 mg, 7.3% yield) as yellow solid. LCMS (ESI): R_(T) (min)=1.398,[M+H]⁺=338.0, method=C; ¹H NMR (400 MHz, CD₃OD) δ 9.20 (s, 1H), 8.27 (s,1H), 7.06 (s, 1H), 6.74 (s, 1H), 5.72-5.68 (m, 1H), 4.07-4.02 (m, 1H),3.53-3.49(m, 1H), 2.65-2.62 (m, 1H), 2.13-2.11 (m, 1H), 1.61-1.53 (m,1H).

Example 87(±)-trans-N-[8-amino-7-(hydroxymethyl)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(Compound 153)

Step 1:(±)-trans-N-[8-amino-7-formyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

A mixture of(±)-trans-N-[8-(benzhydrylideneamino)-7-(difluoromethyl)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(140 mg, 0.25 mmol) and 2,2,2-trifluoroacetic acid (8 mL) in water (20mL) and acetonitrile (20 mL) was stirred at 25° C. for 3 h. The reactionmixture was concentrated and neutralized with sat NaHCO₃ (aq.) topH=7-8. The mixture was concentrated and purified by preparative HPLCRreverse phase (C-18, acetonitrile/Water+0.05% NH₄HCO₃) to give(±)-trans-N-[8-amino-7-formyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(120 mg, 68% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=372.7.

Step 2:(±)-trans-N-[8-amino-7-(hydroxymethyl)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide

To a solution of(±)-trans-N-[8-amino-7-formyl-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(100 mg, 0.16 mmol) in acetonitrile (20 mL) and methyl alcohol (20 mL)at 0° C. was added NaBH₄ (24 mg, 0.63 mmol). The mixture was stirred at0° C. for 10 min. The mixture was concentrated and purified bypreparative reverse phase HPLC (C-18, acetonitrile/Water+0.05% NH₄HCO₃)to give(±)-trans-N-[8-amino-7-(hydroxymethyl)-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(25 mg, 41% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.852,[M+H]⁺=374.1, method=C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 9.46(s, 1H), 8.46 (d, J=4.8 Hz, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.19 (s, 1H),7.34 (d, J=4.8 Hz, 1H), 6.75 (s, 1H), 6.32 (s, 2H), 4.95 (s, 1H), 4.29(d, J=12.4 Hz, 1H), 4.18 (d, J=12.0 Hz, 1H), 2.78-2.75 (m, 1H),2.17-2.11 (m, 1H), 2.08 (s, 3H), 1.61-1.56 (m, 1H), 1.46-1.40 (m, 1H).

Example 88(±)-1-[8-amino-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3-isopropyl-urea(Compound 154)

Step 1: 1-(6-bromo-8-chloro-3-isoquinolyl)-3-isopropyl-urea

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (400 mg, 1.55 mmol),isopropyl isocyanate (1.19 g, 13.98 mmol) and DBU (1.18 g, 7.76 mmol) in1,4-dioxane (15 mL) was stirred at 100° C. for 5 h. The mixture wasconcentrated and purified by column chromatography eluting withEtOAc/hexane=1:2 to afford1-(6-bromo-8-chloro-3-isoquinolyl)-3-isopropyl-urea (570 mg, 1.03 mmol,66% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=342.0.

Step 2:1-[8-chloro-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3-isopropyl-urea

A mixture of 1-(6-bromo-8-chloro-3-isoquinolyl)-3-isopropyl-urea (570mg, 1.03 mmol), 4-methyloxazolidin-2-one (125 mg, 1.24 mmol), Pd₂(dba)₃(95 mg, 0.1 mmol), Xantphos (119 mg, 0.21 mmol) and K₃PO₃ (437 mg, 2.06mmol) in 1,4-dioxane (18 mL) was stirred under Ar at 90° C. for 2 h. Themixture was concentrated and purified by column chromatography elutingwith EtOAc/hexane=2:1 to afford1-[8-chloro-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3-isopropyl-urea(306 mg, 81% yield) as a white solid. LCMS (ESI) [M+H]⁺=363.1.

Step 3: (±)-tert-butylN-[3-(isopropylcarbamoylamino)-6-(4-methyl-2-oxo-oxazolidin-3-yl)-8-isoquinolyl]carbamate

A mixture of1-[8-chloro-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3-isopropyl-urea(286 mg, 0.79 mmol), BocNH₂ (922 mg, 7.88 mmol), Pd₂(dba)₃ (108 mg, 0.12mmol), Brettphos (127 mg, 0.24 mmol) and Cs₂CO₃ (512 mg, 1.58 mmol) in1,4-dioxane (20 mL) was stirred at 90° C. under Ar for 2 h. The mixturewas concentrated and purified by column chromatography eluting withEtOAc/DCM=3:1 to afford tert-butylN-[3-(isopropylcarbamoylamino)-6-(4-methyl-2-oxo-oxazolidin-3-yl)-8-isoquinolyl]carbamate(285 mg, 66% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=444.4.

Step 4:(±)-1-[8-amino-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3sopropyl-urea

A mixture of (±)-tert-butylN-[3-(isopropylcarbamoylamino)-6-(4-methyl-2-oxo-oxazolidin-3-yl)-8-isoquinolyl]carbamate(280 mg, 0.52 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (10 mL) was stirred at 25° C. for 2 h. The reactionmixture was concentrated and neutralized with sat NaHCO₃ (aq.) topH=7-8. The mixture was concentrated and purified by preparative reversephase HPLC (C-18, acetonitrile/water+0.05% NH₄HCO₃) to give(±)-1-[8-amino-6-(4-methyl-2-oxo-oxazolidin-3-yl)-3-isoquinolyl]-3-isopropyl-urea(140 mg, 78% yield) as a yellow solid. LCMS (ESI) R_(T) (min)=1.399,[M+H]⁺=344.2, method=A. ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.80(s, 1H), 7.67 (s, 1H), 7.21 (d, J=6.8 Hz, 1H), 6.87 (d, J=1.2 Hz, 1H),6.84 (s, 1H), 6.25 (s, 2H), 4.71-4.68 (m, 1H), 4.55 (t, J=8.2 Hz, 1H),4.04 (q, J=4.4 Hz, 1H), 3.84-3.78 (m, 1H), 1.28 (d, J=6.4 Hz, 3H), 1.13(d, J=6.8 Hz, 6H).

Example 89N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)acetamide(Compound 155)

Step 1: 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)acetonitrile

A mixture of 2-(1H-pyrazol-5-yl)acetonitrile (250 mg, 2.33 mmol) ,p-toluenesulfonicacid (40 mg, 0.23 mmol) and 3,4-dihydro-2h-pyran (295mg, 3.5 mmol) in ethyl acetate (5 mL) was stirred for 18 hs at 25° C. 5mL saturated aqueous NaHCO₃ was added to reaction mixture and stirredfor 10 min. The EA was dried over Na₂SO₄ and concentrated in vacuo togive 2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetonitrile (430 mg, 74.6%yield) as colorless oil. LCMS (ESI): [M+23]⁺=214.2.

Step 2: 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)acetic acid

A mixture of 2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetonitrile (430 mg,2.25 mmol) and KOH (378. mg, 6.75 mmol) in ethanol (5 mL), water (5 mL)was stirred for 5 hs at 80° C. The EtOH was removed and the resultingmixture diluted with water (10 mL) and extracted with ethyl acetate (10mL). The aqueous phase was adjusted pH=5 with 1N HCl and extracted withethyl acetate (20 mL×2). The combined ethyl acetate layers were driedover Na₂SO₄ and concentrated in vacuo to give2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetic acid (480 mg, 83.7% yield)as colorless oil. LCMS (ESI): [M+H]⁺=233.1.

Step 3: 8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-amine

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (300 mg, 1.17 mmol),4-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (326 mg,1.4 mmol), Na₂CO₃ (309 mg, 2.91 mmol) and Pd(dppf)Cl₂ (43 mg, 0.06 mmol)in 1,4-dioxane (3 mL), H₂O (0.3 mL) was stirred for 3 hrs at 90° C. Thesolvent was removed and the residue was purified by flash columnchromatography (PE:EA=2:1-1:4) to give8-chloro-6-(4-ethyl-3-pyridyl)isoquinolin-3-amine (260 mg , 78.6% yield)as yellow solid.LCMS (ESI): [M+H]⁺=284.1.

Step 4:N-(8-chloro-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)acetamide

To a mixture of 8-chloro-6-(4-ethyl-3-pyridyl)isoquinolin-3-amine (130mg, 0.46 mmol) and 2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetic acid(130 mg, 0.62 mmol) in pyridine (2 mL) was added phosphorus oxychloride(281 mg, 1.83 mmol) at 0° C. The resulting mixture was stirred for 1 hat 0° C. Quenched with sataurated aq.NaHCO₃ and extracted with ethylacetate (20 mL×2). The combined ethyl acetate layers were concentratedin vacuo and the residue was purified by flash column chromatography(PE:EA=3:1-1:3) to giveN-[8-chloro-6-(4-ethyl-3-pyridyl)-3-isoquinolyl]-2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetamide(90 mg, 38.5% yield) as yellow solid. LCMS (ESI): [M+H]⁺=476.2.

Step 5:N-(8-(diphenylmethyleneamino)-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)acetamide

A mixture ofN-[8-chloro-6-(4-ethyl-3-pyridyl)-3-isoquinolyl]-2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetamide(80 mg, 0.17 mmol), benzophenone imine (61 mg, 0.34 mmol), Pd₂(dba)₃ (31mg, 0.03 mmol), Xantphos (39 mg, 0.07 mmol) and Cs₂CO₃ (110 mg, 0.34mmol) in N,N-dimethylformamide (2 mL), toluene (2 mL) was stirred for 3hrs at 130 C. The reaction was cooled to rt, diluted with water, andextracted with ethyl acetate (20 mL×2). The combined ethyl acetatelayers were concentrated in vacuo to giveN-[8-(benzhydrylideneamino)-6-(4-ethyl-3-pyridyl)-3-isoquinolyl]-2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetamide(170 mg , 50.5% yield, crude) as brown solid. This crude was used tonext step without purification. LCMS (ESI):[M+H]⁺=611.2.

Step 6:N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)acetamide

A mixture ofN-[8-(benzhydrylideneamino)-6-(4-ethyl-3-pyridyl)-3-isoquinolyl]-2-(2-tetrahydropyran-2-ylpyrazol-3-yl)acetamide(160 mg, 0.26 mmol) in 1 mL 4 M HCl/dioxane was stirred for 0. 5 h at25° C. The solvent was removed and the residue was purified by reversephase chromatography (acetonitrile 10-45/0.05% NH₄HCO₃ in water) to giveN-[8-amino-6-(4-ethyl-3-pyridyl)-3-isoquinolyl]-2-(1H-pyrazol-5-yl)acetamide(5.3 mg , 5.5% yield) as yellow solid. LCMS (ESI): R_(T) (min)=1.59,[M+H]⁺=373.1, method=C. ¹H NMR (400 MHz, DMSO-d₆): 12.62 (s, 1H), 10.52(s, 1H), 9.31(s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.25 (s,1H), 7.65 (s, 1H), 7.39 (d, J=5.2 Hz, 1H), 6.88 (s, 1H), 6.35 (d, J=6.8Hz, 1H), 6.34 (s, 2H), 6.22 (d, J=6.8 Hz, 1H), 3.83 (s, 2H), 2.64 (q,J=7.6 Hz, 2H), 1.11 (t, J=7.6 Hz, 3H).

Example 90(±)-trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 156)

Step 1: (±)-tert-butyl5-(8-chloro-3-(trans-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-4-methylpyridin-3-ylcarbamate

A mixture of tert-butyl N-(5-bromo-4-methyl-3-pyridyl)carbamate (250 mg,0.87 mmol),[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]boronicacid (350 mg, 1.11 mmol), Na₂CO₃ (185 mg, 1.75 mmol) and Pd(dppf)Cl₂ (35mg, 0.05 mmol) in 1,4-dioxane (10 mL) and H₂O (0.4 mL) was stirred for 4h at 90° C. The reaction was concentrated and purified by flash columnchramotagraphy (PE/EA=20%-60%) to give tert-butylN-[5-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(160 mg, 36.2% yield) as a white solid. LCMS (ESI): [M+H]⁺=478.1.

Step 2: (±)-tert-butylN-[5-[8-(tert-butoxycarbonylamino)-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butyl carbamate (178 mg, 1.52 mmol), tert-butylN-[5-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(160 mg, 0.33 mmol), Pd₃(dba)₂ (30 mg, 0.03 mmol), Brettphos (20 mg,0.04 mmol) and Cs₂CO₃ (320 mg, 0.98 mmol) in 1,4-dioxane (4 mL) wasstirred for 2 h at 90° C. The reaction was then cooled to rt and dilutedwith water (20 mL). The product was extracted with ethyl acetate (50mL×2). The combined ethyl acetate layers were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (PE/EA=40%-70%) to give (±)-tert-butylN-[5-[8-(tert-butoxycarbonylamino)-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(80 mg, 42.78% yield) as yellow solid. LCMS (ESI): [M+H]⁺=559.2.

Step 3:(±)-trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of (±)-tert-butylN-[5-[8-(tert-butoxycarbonylamino)-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate (90 mg, 0.15mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (1 mL)was stirred for 4 h. The reaction was concentrated and purified byprep-HPLC (acetonitrile 5-40%/0.1% NH₄HCO₃ in water) to give(±)-(trans)-N-[8-amino-6-(5-amino-4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(31.4 mg , 60.1% yield) as a yellow solid. LCMS (ESI): R_(T) (min)=1.49,[M+H]⁺=359.1, method=C. ¹H NMR (400 MHz, CD₃OD): 9.25 (s, 1H), 8.28 (s,2H), 7.97 (s , 1H), 7.74 (s, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 2.66-2.64(m, 1H), 2.14 (s, 3H), 2.14-2.11(m, 1H), 1.62-1.54 (m, 2H).

Example 91(±)-4-(8-amino-3-((trans)-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(Compound 157)

Step 1:8-chloro-3-((trans)-2-cyanocyclopropanecarboxamido)isoquinolin-6-ylboronicacid

A mixture of(±)-trans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(200 mg, 0.57 mmol), bis(pinacolato)diboron (174 mg, 0.68 mmol),acetoxypotassium (140 mg, 1.43 mmol) and Pd(dppf)Cl₂ (21 mg, 0.03 mmol)in 1,4-dioxane (4 mL) was stirred in a sealed tube at 80° C. for 3 h.The mixture was concentrated to give(±)-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]boronic acid (150 mg, crude) as a black solid. Thismaterial was use in the next step without purification. LCMS (ESI):[M+H]⁺=316.1.

Step 2:(±)-4-(8-chloro-3-((trans)-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-3-methyl-N-(2,2,2-trifluoroethyl)benzamide

A mixture of crude(±)-[8-chloro-3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]boronicacid (150 mg, 0.48 mmol),4-bromo-3-methyl-N-(2,2,2-trifluoroethyl)benzamide (140 mg, 0.47 mmol),Pd(dppf)Cl₂ (35 mg, 0.05 mmol) and Na₂CO₃ (101 mg, 0.95 mmol) in1,4-dioxane (4 mL), H₂O (0.4 mL) was heated for 3 h. The reaction wasconcentrated and purified by flash column chromatography (PE/EA=40%-70%)to give 4-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-3-methyl-N-(2,2,2-trifluoroethyl)benzamide (120mg, 51.8% yield) as a yellow solid. LCMS (ESI): [M+H]⁺=487.1.

Step 3:(±)-4-(3-(trans-2-cyanocyclopropanecarboxamido)-8-(diphenylmethyleneamino)isoquinolin-6-yl)-3-methyl-N-(2,2,2-trifluoroethyl)benzamide

A mixture of4-[8-chloro-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(100 mg, 0.21 mmol), benzophenone imine (75 mg, 0.41 mmol), Cs₂CO₃ (134mg, 0.41 mmol), Pd₂(dba)₃ (38 mg, 0.04 mmol) and Xantphos (48 mg, 0.08mmol) in N,N-dimethylformamide (3mL) and toluene (1 mL) was stirred at140° C. for 3 h. The reaction was cooled to rt, diluted with water (10mL) and extracted with EA (20 mL×2). The combined EA extracts wereconcentrated in vacuo to give crude4-[8-(benzhydrylideneamino)-3-[[(1R,2R)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(240mg1, 65.8% yield) as a brown oil. This crude material was used inthe next step without purification. LCMS (ESI): [M+H]⁺=632.2.

Step 4:(±)-4-(8-amino-3-((trans)-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-3-methyl-N-(2,2,2-trifluoroethyl)benzamide

To a solution of(±)-4-[8-(benzhydrylideneamino)-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(240 mg, 0.14 mmol) in N,N-dimethylformamide (2 mL) and H₂O (0.5 mL) wasadded 2 drops of TFA. The resulting mixture was stirred for 1 h. Thisreaction mixture was purified by prep-HPLC (acetonitrile 20-50%/0.1%NH₄HCO₃ in water) to give(±)-4-[8-amino-3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-isoquinolyl]-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(16.4 mg, 26% yield) as yellow solid.

LCMS (ESI): R_(T) (min)=1.80, [M+H]⁺=468.1, method=C. ¹H NMR (400 MHz,CD₃OD): 9.25 (s, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 7.76 (d, J=7.6 Hz,1H), 7.40 (d, J=7.6 Hz, 1H), 6.97 (s, 1H), 4.17-4.10 (m, 2H), 2.67-2.62(m, 1H), 2.36 (s, 3H), 2.14-2.09 (m, 1H), 1.62-1.52 (m, 2H).

Example 92(±)-trans-N-(8-amino-6-(4-methyl-2-oxooxazol-3(2H)-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 159)

Step 1: 6-bromo-8-chloro-N,N-bis(4-methoxybenzyl)isoquinolin-3-amine

To a solution of NaH (1.25 g, 31 mmol) in N,N-Dimethylformamide (50 mL)was added 6-bromo-8-chloro-isoquinolin-3-amine (2.0 g, 7.77 mmol) andthe resulting mixture was stirred for 30 min at 0° C. 4-Methoxybenzylchloride (2.2 mL, 16 mmol) was added. The mixture was stirred overnightat room temperature. The mixture was quenched with sat. NH₄Cl anddiluted with ethyl acetate (200 mL). The resulting mixture was washedwith water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EA:PE=1:10) to give6-bromo-8-chloro-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine(2.8 g, 72% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=497.1.

Step 2: tert-butyl3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-6-ylcarbamate

A mixture of Pd₂(dba)₃ (0.94 g, 1.0 3 mmol), Xantphos (1.12 g, 1.94mmol), K₂CO₃ (1.87 g, 13.55 mmol), tert-butyl carbamate (1.4 g, 11.95mmol) and 6-bromo-8-chloro-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine (2.8 g, 5.62 mmol) in 1,4-dioxane (100 mL)was stirred overnight at 90° C. under Ar. The mixture was directlypurified by silica gel column chromatography (EA:PE=1:10 to 1:8) to givetert-butylN-[3-[bis[(4-methoxyphenyl)methyl]amino]-8-chloro-6-isoquinolyl]carbamate(2.4 g, 80% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=534.2.

Step 3: 8-chloro-N3,N3-bis(4-methoxybenzyl)isoquinoline-3,6-diamine

A solution of tert-butylN-[3-[bis[(4-methoxyphenyl)methyl]amino]-8-chloro-6-isoquinolyl]carbamate(2.4 g, 4.49 mmol) and Cs₂CO₃ (4.8 g, 14.72 mmol) in 1,4-dioxane (40 mL)and N,N-dimethylformamide (40 mL) was stirred overnight at 130° C. Themixture was diluted with ethyl acetate (100 mL) and washed with waterand brine. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (EA:PE=1:2) to give8-chloro-N3,N3-bis[(4-methoxyphenyl)methyl]isoquinoline-3,6-diamine (900mg, 46% yield) as a red solid. LCMS (ESI) [M+H]⁺=434.2.

Step 4: 2-oxopropyl3-(bis(4-methoxybenzyl)amino)-8-chloroisoquinolin-6-ylcarbamate

To a stirred solution of triphosgene (1.2 g, 4.04 mmol) intetrahydrofuran (20 mL) was added a solution of triethylamine (3 mL,21.52 mmol) and8-chloro-N3,N3-bis[(4-methoxyphenyl)methyl]isoquinoline-3,6-diamine (900mg, 2.07 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture wasstirred at 0° C. for 1 h followed by the addition of hydroxyacetone (2.0g, 27 mmol). The reaction mixture was stirred at room temperatureovernight. The mixture was diluted with ethyl acetate (100 mL) andwashed with brine. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column (EA:PE=1:2) to give acetonylN-[3-[bis[(4-methoxyphenyl)methyl]amino]-8-chloro-6-isoquinolyl]carbamate(650 mg, 59% yield) as a brown solid. LCMS (ESI) [M+H]⁺=534.2.

Step 5:3-(8-chloro-3-(4-methoxybenzylamino)isoquinolin-6-yl)-4-methyloxazol-2(3H)-one

A solution of acetonylN-[3-[bis[(4-methoxyphenyl)methyl]amino]-8-chloro-6-isoquinolyl]carbamate(640 mg, 1.2 mmol) in acetic acid (40 mL) was heated to 120° C. for 2 h.After the solvent was evaporated, the residue was dissolved indichloromethane (10 mL) and 2,2,2-trifluoroacetic acid (2 mL) andcontinued to stir for 1 h at room temperature. The reaction wasconcentrated to give crude3-[8-chloro-3-[(4-methoxyphenyl)methylamino]-6-isoquinolyl]-4-methyl-oxazol-2-one(430 mg, 91% yield) as a red oil, which was directly used in the nextreaction. LCMS (ESI) [M+H]⁺=396.1.

Step 6: 3-(3-amino-8-chloroisoquinolin-6-yl)-4-methyloxazol-2(3H)-one

A solution of3-[8-chloro-3-[(4-methoxyphenyl)methylamino]-6-isoquinolyl]-4-methyl-oxazol-2-one(430 mg, 1.09 mmol) in 2,2,2-trifluoroacetic acid (8 mL) was heated at45° C. for 1 h. The reaction was concentrated and the residue wasre-dissolved in DCM (50 mL) and washed with sat. sodium bicarbonate andbrine. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EA:PE=1:2 to EA:DCM=1:1) to give3-(3-amino-8-chloro-6-isoquinolyl)-4-methyl-oxazol-2-one (160 mg, 53%yield) as a red solid. LCMS (ESI) [M+H]⁺=276.0.

Step 7: (±)-trans-N-(8-chloro-6-(4-methyl-2-oxooxazol-3(2H)-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

(COCl)₂ (0.09 mL, 1.06 mmol) was added dropwise to a suspension of(±)-trans-2-cyanocyclopropanecarboxylic acid (50 mg, 0.45 mmol) and DMF(3 mg, 0.04 mmol) in dichloromethane (5 mL) at 0° C. The mixture wasstirred at room temperature for another 1 h. The mixture was evaporatedat room temperature to remove most of the DCM and (COCl)₂. The residuewas suspended in DCM (5 mL) and was added dropwise to a mixture of3-(3-amino-8-chloro-6-isoquinolyl)-4-methyl-oxazol-2-one (80 mg, 0.29mmol) and pyridine (0.5 mL, 6.18 mmol) in dichloromethane (5 mL) at 0°C. The reaction mixture was stirred at 0° C. for another 0.5 h. Thereaction mixture was diluted with DCM (50 mL), washed with H₂O (20 mL).The organic layer was separated, dried over Na₂SO₄, filtered andevaporated. The residue was purified by silica gel chromatography(EA:PE=1:2) to give(±)-(trans)-N-[8-chloro-6-(4-methyl-2-oxo-oxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(40 mg, 37% yield) as a light yellow solid. LCMS (ESI) [M+H]⁺=369.1.

Step 8: tert-butyl3-(trans-2-cyanocyclopropanecarboxamido)-6-(4-methyl-2-oxooxazol-3(2H)-yl)isoquinolin-8-ylcarbamate

A mixture of tert-butyl carbamate (230 mg, 1.96 mmol), Pd₂(dba)₃ (35 mg,0.04 mmol), Brettphos (35 mg, 0.07 mmol), Cs₂CO₃ (210 mg, 0.64 mmol) andtrans-N-[8-chloro-6-(4-methyl-2-oxo-oxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(70 mg, 0.19 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 2days under Ar. The mixture was directly purified by silica gel column(EA:PE=1:1 to 100% EA) to give (±)-tert-butylN-[3-[[(trans)-2-cyanocyclopropanecarbonyl]amino]-6-(4-methyl-2-oxo-oxazol-3-yl)-8-isoquinolyl]carbamate(35 mg, 41% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=450.1.

Step 9:trans-N-(8-amino-6-(4-methyl-2-oxooxazol-3(2H)-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A solution of tert-butylN-[3-[[trans-2-cyanocyclopropanecarbonyl]amino]-6-(4-methyl-2-oxo-oxazol-3-yl)-8-isoquinolyl]carbamate(30 mg, 0.07 mmol) in dichloromethane (4 mL) and 2,2,2-trifluoroaceticacid (1 mL) was stirred for 1 h at room temperature. After the reactionwas concentrated, the residue was neutralized by ammonium in MeOH. Theresulting mixture was purified by reverse phase chromatography(acetonitrile 17-47/0.05% sodium bicarbonate in water) to give(±)-(trans)-N-[8-amino-6-(4-methyl-2-oxo-oxazol-3-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(2.7 mg, 12% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.572,[M+H]⁺=350.1, method=C; ¹H-NMR (400 MHz, CD₃OD): δ 9.26 (s, 1H), 8.33(s, 1H), 7.02 (s, 1H), 6.65 (s, 1H), 4.65 (s, 1H), 2.67-2.62 (m, 1H),2.15-2.09 (m, 1H), 2.01 (s, 3H), 1.62-1.52 (m, 2H).

Example 93(±)-trans-N-(8-amino-6-(2-methyl-6-oxopiperazin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 160)

Step 1: tert-butyl 3-methyl-5-oxopiperazine-1-carboxylate

A mixture of 6-methylpiperazin-2-one (200 mg, 1.75 mmol), (Boc)₂O (420mg, 1.93 mmol) and Na₂CO₃ (370 mg, 3.49 mmol) in 1,4-dioxane (8 mL) andwater (2 mL) was stirred at 25° C. for 4 h. The reaction was dilutedwith water (10 ml) and EtOAc (20 ml). The organics were then separatedand dried (Na₂SO₄). The residue was concentrated to give tert-butyl3-methyl-5-oxo-piperazine-1-carboxylate (350 mg, 93.2% yield) as a whitesolid. LCMS (ESI) [M+H]⁺=215.1.

Step 2: tert-butyl4-(8-chloro-3-(trans-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate

A mixture oftrans-N-(6-bromo-8-chloro-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(200 mg, 0.57 mmol), Pd₂(dba)₃ (100 mg, 0.11 mmol), Xantphos (130 mg,0.22 mmol), K₃PO₄ (360 mg, 1.7 mmol) andtert-butyl-3-methyl-5-oxo-piperazine-1-carboxylate (170 mg, 0.79 mmol)in 1,4-dioxane (15 mL) was stirred at 90° C. for 3 h under Ar.

The mixture was directly purified by silica gel column (EA:PE=1:2 to1:1) to give tert-butyl4-[8-chloro-3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]-3-methyl-5-oxo-piperazine-1-carboxylate(100 mg, 36.2% yield) as a white solid. LCMS (ESI) [M+H]⁺=484.1.

Step 3: tert-butyl4-(8-(tert-butoxycarbonylamino)-3-(trans-2-cyanocyclopropanecarboxamido)isoquinolin-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate

A mixture of tert-butyl carbamate (200 mg, 1.71 mmol), Pd₂(dba)₃ (32 mg,0.03 mmol), Brettphos (20 mg, 0.04 mmol), Cs₂CO₃ (160 mg, 0.49 mmol) andtert-butyl4-[8-chloro-3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]-3-methyl-5-oxo-piperazine-1-carboxylate(80 mg, 0.17 mmol) in 1,4-dioxane (10 mL) was stirred at 90° C. for 3 hunder Ar. The mixture was directly purified by silica gel column(EA:PE=2:1 to 4:1) to give tert-butyl4-[8-(tert-butoxycarbonylamino)-3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]-3-methyl-5-oxo-piperazine-1-carboxylate(50 mg, 0.09 mmol, 53.6% yield) as a yellow solid. LCMS (ESI)[M+H]⁺=565.1.

Step 4:trans-N-(8-amino-6-(2-methyl-6-oxopiperazin-1-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

To a solution of tert-butyl4-[8-(tert-butoxycarbonylamino)-3-[(trans-2-cyanocyclopropanecarbonyl)amino]-6-isoquinolyl]-3-methyl-5-oxo-piperazine-1-carboxylate(40 mg, 0.07 mmol) dissolved in dichloromethane (4 mL) was added TFA (2mL, 0.14 mmol). The mixture was stirred at room temperature for 2 h. Thereaction was concentrated to dryness. The residue was purified byreverse phase chromatography (acetonitrile 0-50/0.1% NH₄HCO₃ in water)to affordtrans-N-[8-amino-6-(2-methyl-6-oxo-piperazin-1-yl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(9.7 mg, 37.6% yield) as a white solid. LCMS (ESI): R_(T) (min)=1.35,[M+H]⁺=365.1, method=C; ¹HNMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 9.27(s, 1H), 8.16(s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 6.30 (s, 2H),4.05-3.92 (m, 2H), 3.17-3.12 (m, 2H), 2.78-2.74 (m, 3H), 2.17-2.11 (m,1H), 1.61-1.56 (m, 1H), 1.45-1.42 (m, 1H), 1.01 (d, J=6.4 Hz, 3H).

Example 94(±)-trans-N-(8-amino-7-fluoro-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 161)

Step 1:trans-N-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of (±)-trans-2-cyanocyclopropanecarboxylic acid (290 mg, 2.61mmol), oxalyl dichloride (0.2 mL, 2.36 mmol) in DCM (3 mL) and one dropDMF was stirred for 0.5 h. The reaction mixture was concentrated. To asolution of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (700 mg, 2.17mmol) in DCM(7 mL) and pyridine (0.5 mL) was added the concentrated acidchloride mixture in portions at room temperature. The mixture wasstirred for 1 h. The reaction was concentrated to dryness and theresidue was taken up in EtOAc (50 mL) and adjusted pH to 7-8 with satNaHCO_(3.)The organic layer was washed with100 mL saturated brinesolution. The organics were then separated and dried (NaSO₄) beforeconcentration to dryness. The residue was purified with silicachromatography (PE:EA=2:1 to PE:EA=1:1) to give the title compound as ayellow solid (730 mg, 40.2% yield). LCMS (ESI) [M+H]+=416.0.

Step 2:trans-N-(8-chloro-7-fluoro-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture oftrans-N-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide(730 mg, 1.76 mmol), (4S)-4-methyloxazolidin-2-one (270 mg, 2.67 mmol),CuI (667 mg, 3.51 mmol), N1,N2-dimethylethane-1,2-diamine (616 mg, 7mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 3 h under Ar. Thereaction was concentrated to dryness. The residue was purified withsilica gel chromatography (PE:EA=4:1 to PE:EA=1:1) to give the titlecompound as a yellow solid (460 mg, 40.9% yeild) in the end. LCMS (ESI)[M+H]+=389.1.

Step 3: tert-butyl3-(trans-2-cyanocyclopropanecarboxamido)-7-fluoro-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-8-ylcarbamate

A mixture oftrans-N-[8-chloro-7-fluoro-6-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide(450 mg, 1.16 mmol), tert-butyl carbamate (1.3 g, 11.1 mmol), Brettphos(120 mg, 0.22 mmol), Pd₂(dba)₃ (210 mg, 0.23 mmol), and Cs₂CO₃ (1.1 g,3.37 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 3 h under Ar.The reaction was concentrated to dryness. The residue was purified bysilica gel chromatography (PE:EA=4:1 to PE:EA=1:1) to give the titlecompound as a white solid (55 mg, 6.2% yield). LCMS (ESI) [M+H]+=470.2

Step 4:trans-N-(8-amino-7-fluoro-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide

A mixture of tert-butylN-[3-[[trans-2-cyanocyclopropanecarbonyl]amino]-7-fluoro-6-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-8-isoquinolyl]carbamate(55 mg, 0.12 mmol), TFA (0.5 mL, 0.12 mmol) in dichloromethane (2 mL)was stirred at room temperature for 1 h. The reaction was concentratedto dryness and the residue was taken up in MeOH (2 mL) and adjusted pHto 7-8 with sat NaHCO₃. The mixture was purified by prep-HPLC (5%-95%methanol and 0.8 g/L NH₄HCO₃ in water) to give the title compound as ayellow solid (16.7 mg, 37.8% yield.) LCMS (ESI): RT(min)=1.65,[M+H]+=370.1, Method=B. ¹HNMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.39(s, 1H), 8.22 (s, 1H), 7.06 (d, J=6.4 Hz, 1H), 6.39 (s, 2H), 4.67 (t,J=8.0 Hz, 1H), 4.53 (d, J=7.2 Hz, 1H), 4.06 (t, J=8.0 Hz, 1H), 2.75-2.71(m, 1H), 2.15-2.12 (m, 1H), 1.61-1.57 (m, 1H), 1.42-1.40 (m, 1H), 1.15(d, J=6.0 Hz, 3H).

Example 95(1S,2S)—N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 162) and(1R,2R)-N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 163)

The title compounds were prepared using procedures as described for(±)-trans-N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide.The single enantiomers were isolated by chiral SFC. Compound 162: LCMS(ESI): RT(min)=3.83, [M+H]+=400.1, Method=J. Compound 163: LCMS (ESI):RT(min)=3.83, [M+H]+=400.1, Method=J.

Example 96(1S,2S)—N-(8-amino-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(Compound 164)

The title compound was prepared using a procedure as described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). ¹HNMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 9.19 (s, 1H),8.19 (s, 1H), 7.0 (s, 1H), 6.93 (s, 1H), 4.84-5.02 (m, 1H), 4.58-4.72(m, 1H), 4.56 (t, 1H), 4.04-4.07 (m, 1H), 2.23-2.51 (m, 1H), 1.63-1.70(m, 1H), 1.14-1.3 (m, 4H)

Example 97(1S,2R)—N-(8-amino-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(Compound 165)

The title compound was prepared using a procedure as described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). LCMS (ESI): RT(min)=1.52, [M+H]+=345.2, Method=B.

Example 98(1S,2S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 166) and(1R,2R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 167)

The title compound was prepared using a procedure as described for(±)-trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 156). The single isomers were isolated by chiral SFC. Compound166: ¹HNMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.32 (s, 1H), 8.21 (s,1H), 7.94 (s, 1H), 7.64 (s, 1H), 6.82 (s, 1H), 6.53 (s, 1H), 6.31 (s,2H), 5.18 (s, 1H), 2.73-2.77 (m, 1H), 2.12-2.14 (m, 1H), 1.59-1.61 (m,1H), 1.40-1.57 (m, 1H). LCMS (ESI): RT(min)=2.48, [M+H]+=359.1,method=J. Compound 167: ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.31(s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 6.82 (s, 1H), 6.53(s, 1H), 6.31 (s, 2H), 5.18 (s, 1H), 2.73-2.77 (m, 1H), 2.12-2.14 (m,1H), 1.59-1.61 (m, 1H), 1.40-1.57 (m, 1H). LCMS (ESI): RT(min)=2.48,[M+H]+=359.1, Method=J.

Example 99(1S,2S)—N-(8-amino-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 168) and(1R,2R)—N-(8-amino-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 169)

The title compound was prepared using a procedure as described for(±)-trans-N-(8-amino-6-(4-methylisothiazol-5-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 62). The single isomers were separated by chiral SFC. Compound168: ¹HNMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 3.34 (s, 1H), 8.48 (s,H), 8.29 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 6.55 (s, 2H), 2.74-2.76(m, 1H), 2.40 (s, 3H), 2.08-2.17 (m, 1H), 1.62-1.63 (m, 1H), 1.40-1.45(m, 1H). LCMS (ESI): RT(min)=4.66, [M+H]+=350.1, Method=J. Compound 169:¹H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 3.34 (s, 1H), 8.48 (s, H),8.29 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 6.55 (s, 2H), 2.74-2.76 (m,1H), 2.40 (s, 3H), 2.08-2.17 (m, 1H), 1.62-1.58 (m, 1H), 1.40-1.45 (m,1H).). LCMS (ESI): RT(min)=4.66, [M+H]+=350.1, Method=J.

Example 100(±)-trans-N-(8-amino-6-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 170)

The title compound was prepared using procedures that are analogeous tothe one described for(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide (Compound 123). 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.34(s, 1H), 8.86 (s, 1H), 8.29 (d, J=9.8 Hz, 2H), 7.66 (d, J=3.1 Hz, 1H),7.22 (s, 1H), 7.00 (d, J=1.5 Hz, 1H), 6.68 (dd, J=3.0, 0.8 Hz, 1H), 6.37(s, 2H), 3.97 (s, 3H), 2.80-2.73 (m, 1H), 2.17-2.11 (m, 1H), 1.63-1.55(m, 1H), 1.48-1.40 (m, 1H). LCMS (ESI): RT(min)=2.76, [M+H]+=383.1,Method=J.

Example 101(±)-trans-N-(8-amino-6-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 171)

The title compound was prepared using procedures that are analogous tothe one described for(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide (Compound 123). 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.36(s, 1H), 9.20 (s, 1H), 8.47 (s, 1H), 8.40-8.29 (m, 2H), 7.34 (s, 1H),7.06 (d, J=1.5 Hz, 1H), 6.44 (s, 2H), 4.24 (s, 3H), 2.77 (dd, J=10.8,8.0 Hz, 1H), 2.19-2.09 (m, 1H), 1.65-1.56 (m, 1H), 1.49-1.39 (m, 1H).LCMS (ESI): RT(min)=3.09, [M+H]+=384.1, Method=J.

Example 102(±)-trans-N-(8-amino-6-(2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 172)

The title compound was prepared using procedures that are analogous tothe one described for(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide (Compound 123). 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.35(s, 1H), 9.15 (s, 1H), 8.76 (s, 1H), 8.32 (d, J=14.3 Hz, 2H), 7.33 (s,1H), 7.02 (d, J=1.5 Hz, 1H), 6.39 (s, 2H), 4.30 (s, 3H), 2.75 (d, J=5.9Hz, 1H), 2.19-2.09 (m, 1H), 1.64-1.55 (m, 1H), 1.49-1.39 (m, 1H). LCMS(ESI): RT(min)=2.70, [M+H]+=384.1, Method=J.

Example 103(±)-trans-N-(8-amino-6-(5,5-dimethyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 173)

The title compound was prepared using procedures that are analogous tothe one described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.19 (s, 1H),8.12 (s, 1H), 7.21 (d, J=2.1 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 6.34 (s,2H), 3.89 (s, 2H), 2.74 (dd, J=11.4, 7.2 Hz, 1H), 2.18-2.09 (m, 1H),1.60-1.55 (m, 1H), 1.48 (s, 6H), 1.42 (dt, J=10.2, 5.1 Hz, 1H). LCMS(ESI): RT(min)=3.58, [M+H]+=366.1, Method=J.

Example 104trans-N-(8-amino-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 174)

The title compound was prepared using procedures that are analogeous tothe one described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.21 (s, 1H),8.15 (s, 1H), 7.00 (s, 2H), 6.35 (s, 2H), 4.63 (dd, J=8.4, 4.1 Hz, 1H),4.42 (t, J=8.9 Hz, 1H), 4.29 (dd, J=9.0, 4.0 Hz, 1H), 2.73 (d, J=12.9Hz, 1H), 2.16-2.07 (m, 2H), 1.61-1.55 (m, 1H), 1.42 (dt, J=9.3, 4.7 Hz,1H), 0.88 (d, J=7.0 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). LCMS (ESI):RT(min)=3.89, [M+H]+=380.1, Method=J.

Example 105trans-N-(8-amino-6-((R)-4-isopropyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 175)

The title compound was prepared using procedures that are analogeous tothe one described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.21 (s, 1H),8.15 (s, 1H), 7.00 (s, 2H), 6.35 (s, 2H), 4.69-4.59 (m, 1H), 4.42 (t,J=8.9 Hz, 1H), 4.30 (dd, J=8.9, 4.0 Hz, 1H), 2.79-2.69 (m, 1H),2.18-2.06 (m, 2H), 1.64-1.54 (m, 1H), 1.46-1.37 (m, 1H), 0.88 (d, J=7.0Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). LCMS (ESI): RT(min)=3.98, [M+H]+=380.2,method=J.

Example 106(±)-trans-N-(8-amino-6-(2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 176)

The title compound was prepared using procedures that are analogeous tothe one described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.19 (s, 1H),8.14 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 6.35 (s,2H), 4.47-4.40 (m, 2H), 4.13-4.06 (m, 2H), 2.78-2.71 (m, 1H), 2.17-2.08(m, 1H), 1.61-1.54 (m, 1H), 1.46-1.38 (m, 1H). LCMS (ESI): RT(min)=3.02,[M+H]+=338.1, Method=J.

Example 107(±)-trans-N-(8-amino-6-(2-oxotetrahydro-2H-cyclopenta[d]oxazol-3 (3aH)-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide (Compound177)

The title compound was prepared using procedures that are analogeous tothe one described for(1S,2S)—N-(8-amino-6-((S)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide(Compound 128). 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.19 (s, 1H),8.14 (s, 1H), 7.16 (d, J=2.0 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.35 (s,2H), 5.14-5.04 (m, 1H), 4.89 (s, 1H), 2.73 (d, J=5.3 Hz, 1H), 2.16-2.08(m, 1H), 2.01-1.93 (m, 1H), 1.86-1.76 (m, 3H), 1.68 (s, 1H), 1.63-1.52(m, 2H), 1.42 (d, J=4.3 Hz, 1H). LCMS (ESI): RT(min)=3.73, [M+H]+=378.1,Method=J.

Example 108(±)-trans-N-(8-amino-6-(N,N-dimethylsulfamoyl)isoquinolin-3-yl)cyclopropane-1,2-dicarboxamide(Compound 178)

LCMS (ESI): RT(min)=3.32, [M+H]+=378.1, Method=N*.

Example 109(±)-trans-N-(8-amino-6-(N,N-dimethylsulfamoyl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 179)

LCMS (ESI): RT(min)=3.39, [M+H]+=369.1, Method=N*.

Example 110(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 180) and(1R,2R)-N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 181)

Step 1: 4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-amine

A mixture of 2-chloro-4-methylpyridin-3-amine (5.0 g, 35 mmol),(1-methyl-1H-pyrazol-5-yl)boronic acid (13.25 g, 105.2 mmol), K3PO4(22.33 g, 105.20 mmol), and Pd(dppf)Cl₂ (2.57 g, 3.51 mmol) in 10:1dioxane/water (110 mL) was heated at 100° C. After 3 h, the solids werefiltered, and the filtrate was concentrated in vacuo. Purification ofthe resulting residue by flash column chromatography (3:2 petroleumether/ethyl acetate) afforded4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-amine (2.0 g, 30% yield)as a brown solid. LCMS (ESI) [M+H]⁺=189.

Step 2: 3-iodo-4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridine

To an ice-cooled solution of4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-amine (0.50 g, 2.7 mmol),t-BuNO₂ (1.09 g, 10.6 mmol) in CH₃CN (10 mL) was added CuI (2.02 g, 10.6mmol). The resulting mixture was warmed to room temperature. After 16 h,the reaction was sequentially diluted with ammonium hydroxide (10 mL)and water (10 mL). The resulting solution was extracted withdichloromethane (20 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by flash columnchromatography (3:1 ethyl acetate/petroleum ether) provided3-iodo-4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridine (0.30 g, 38%) as ayellow solid. LCMS (ESI) [M+H]⁺=300.

Step 3:8-chloro-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-3-amine

A mixture of (3-amino-8-chloroisoquinolin-6-yl)boronic acid (892 mg,4.01 mmol), 3-iodo-4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridine (0.60g, 2.0 mmol), Pd(dppf)Cl₂ (147 mg, 0.20 mmol), AcONa (164 mg, 2.01mmol), and K₃PO₄ (1.28 g, 6.02 mmol) in 10:1 1,4-dioxane/water (22 mL)was heated at 100° C. After 2 h, the solids were filtered, and thefiltrate was concentrated in vacuo. Purification by flash columnchromatography (ethyl acetate) gave8-chloro-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-3-amine(0.70 g, 74% yield) as a dark red solid. LCMS (ESI) [M+H]⁺=350.

Step 4:trans-N-[8-Chloro-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

To an ice-cooled solution of8-chloro-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-3-amine(632 mg, 1.81 mmol),trans-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid (0.20g, 1.2 mmol) and pyridine (6.00 mL) in dichloromethane (40.00 mL) wasadded POCl₃ (277 mg, 1.81 mmol) dropwise. The mixture was warmed to roomtemperature. After 30 min, excess POCl₃ was quenched with water (30 mL).The resulting solution was extracted with dichloromethane (100 mL). Thecollected organic was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford crudetrans-N-[8-chloro-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(0.60 g) as a dark red solid. LCMS (ESI) [M+H]⁺=498.

Step 4: Trans-tert-butylN-(3-[[2-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-8-yl)carbamate

A suspension oftrans-N-[8-chloro-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(0.80 g, 1.61 mmol), tert-butyl carbamate (3.76 g, 32.1 mmol), Pd₂(dba)₃(294 mg, 3.21 mmol), BrettPhos (302 mg, 0.56 mmol), and t-BuONa (386 mg,4.03 mmol) in dioxane (20 mL) was heated at 90° C. After 16 h, thesolids were filtered, and the filtrate was concentrated in vacuo.Purification by flash column chromatography (ethyl acetate) affordedtrans-tert-butylN-(3-[[2-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-8-yl)carbamate(350 mg, 38% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=579.

Step 5:(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamideand(1R,2R)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide

To a solution of trans-tert-butylN-(3-[[2-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-[4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]isoquinolin-8-yl)carbamate(0.30 g, 0.52 mmoL) in N,N-dimethylformamide (2.0 mL) was added HCl (5mL, 4M in dioxane) at room temperature. After 1 h, the reaction wasconcentrated in vacuo. Purification of crude material by Prep-HPLCafforded the racemic product (60 mg, 24%) as a light yellow solid. Theenantiomers were separated by chiral SFC. Compound 180:¹HNMR (400 MHz,CD₃OD) δ 9.17 (s, 1H), 8.56 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 7.49 (d,J=5.7 Hz, 2H), 7.37 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 6.82 (s, 1H),6.47(d, J=1.3 Hz, 1H), 5.99 (d, J=2.0 Hz, 1H), 3.86 (s, 3H), 3.81 (s,3H), 2.38-2.33 (m, 1H), 2.29 (s, 3H), 2.12-2.04 (m, 1H), 1.57-1.53(m,1H), 1.30-1.18 (m, 1H). LCMS (ESI): RT(min)=1.23, [M+H]+=479,Method=K. Compound 181: ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.56 (d,J=5.1 Hz, 1H), 8.20 (s, 1H), 7.49 (d, J=5.7 Hz, 2H), 7.37 (s, 1H), 7.20(d, J=2.0 Hz, 1H), 6.82 (s, 1H), 6.47 (d, J=1.3 Hz, 1H), 5.99(d, J=2.0Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.38-2.33 (m, 1H), 2.29 (s, 3H),2.12-2.04 (m, 1H), 1.57-1.53 (m, 1H), 1.30-1.18 (m, 1H). LCMS (ESI):RT(min)=1.22, [M+H]⁺=479, Method=K.

Example 111(1R,2R)-N-(8-amino-6-(4-methyl-2-phenylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 182) and(1S,2S)—N-(8-amino-6-(4-methyl-2-phenylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 183)

The title compound was prepared by following the procedure as describedfor(1S,2S)-N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 180) and making slight variations. The enantiomers wereisolated by chiral SFC. Compound 182: ¹HNMR (300 MHz, CD₃OD) δ 9.14 (s,1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.50 (s, 1H), 7.44-7.26 (m, 4H),7.22-7.11 (m, 3H), 6.78 (s, 1H), 6.50 (d, J=1.3 Hz, 1H), 3.85 (d, J=0.6Hz, 3H), 2.41-2.31 (m, 1H), 2.27 (s, 3H), 2.13-2.04 (m, 1H), 1.56-1.53(m, 1H), 1.32-1.17 (m, 1H). LCMS (ESI): RT(min)=1.13, [M+H]+=474,Method=K. Compound 183; ¹HNMR (300 MHz, CD3OD) δ 9.14 (s, 1H), 8.47 (s,1H), 8.13 (s, 1H), 7.50 (s, 1H), 7.44-7.26 (m, 4H), 7.22-7.11 (m, 3H),6.78 (s, 1H), 6.50 (d, J=1.3 Hz, 1H), 3.85 (s, 3H), 2.41-2.31 (m, 1H),2.27 (s, 3H), 2.13-2.04 (m, 1H), 1.56-1.53 (m, 1H), 1.32-1.17 (m, 1H).LCMS (ESI): RT(min)=1.13, [M+H]+=474, Method=K.

Example 112(±)-trans-N-(8-amino-6-(4-methyl-2-(piperidin-1-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 184)

The title compound was prepared by following the procedure as describedfor(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 180) but substituting3-bromo-4-methyl-2-(piperidin-1-yl)pyridine and making slightvariations.¹HNMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 9.27 (s, 1H), 8.24(s, 1H), 8.06 (d, J=5.0 Hz, 1H), 7.56 (s, 1H), 7.29 (d, J=0.8 Hz, 1H),6.94-6.80 (m, 2H), 6.53 (d, J=1.4 Hz, 1H), 6.20 (s, 2H), 3.78 (s, 3H),2.96 (s, 4H), 2.19 (t, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.36 (qd, J=7.0,6.2, 4.3Hz, 3H), 1.25 (d, J=8.3Hz, 4H), 1.20-1.10 (m, 1H). LCMS (ESI):RT (min)=2.02, [M+H]+=482.3, Method=K.

Example 113(±)-trans-N-(8-amino-6-(2-amino-3-methylpyridin-4-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 185)

The title compound was prepared by following the procedure as describedfor(±)-trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 156) and making slight variations. ¹HNMR (300 MHz, DMSO-d₆) δ10.75 (s, 1H), 9.30 (s, 1H), 8.27 (s, 1H), 7.83 (d, J=5.1 Hz, 1H), 7.57(d, J=0.9 Hz, 1H), 7.30 (d, J=0.8 Hz, 1H), 6.81 (d, J=1.3 Hz, 1H),6.53-6.41 (m, 2H), 6.31 (s, 2H), 5.78 (s, 2H), 3.78 (s, 3H), 2.20-2.16(m, 2H), 1.98 (s, 3H), 1.44-1.32 (m, 1H), 1.17-1.14 (m, 1H). LCMS (ESI):RT (min)=1.05, [M+H]+=414.1, Method=K.

Example 114(±)-trans-N-(8-amino-6-[4-methyl-5-[(propan-2-yl)amino]pyridin-3-yl]isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide(Compound 186)

The title compound was prepared by following the procedure as describedfor(±)-trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 156) and making slight variations. ¹HNMR (300 MHz, CD₃OD) δ9.26 (s, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 6.97 (s, 1H),6.68 (d, J=1.4 Hz, 1H), 3.83-3.80 (m, 1H), 2.71-2.60 (m, 1H), 2.18-2.03(m, 4H), 1.58-1.54 (m, 2H), 1.33 (d, J=12 Hz, 6H). LCMS (ESI): RT(min)=1.03, [M+H]+=401.1, Method=K.

Example 115(±)-trans-(1S,2R)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)cyclopropanecarboxamide(Compound 187)

The title compound was prepared by following the procedure as describedfor(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 180) and making slight variations. ¹H NMR (300 MHz, CD₃OD) δ9.28 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.35 (s, 1H), 7.26(d, J=5.1 Hz, 1H), 7.15 (s, 1H), 6.88 (s, 1H), 6.53 (s, 1H), 3.71 (s,3H), 2.83-2.59 (m, 2H), 2.18 (t, J=0.7 Hz, 3H), 2.01 (dt, J=8.7, 4.5 Hz,1H), 1.85-1.58 (m, 1H), 1.33 (dt, J=9.0, 4.7 Hz, 1H), 1.07-1.00 (m, 1H).LCMS (ESI): RT (min)=1.207, [M+H]+=438.2, Method=K.

Example 116N-(8-Amino-6-(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(Compound 188)

Step 1: tert-Butyl4-(3-amino-8-chloroisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a mixture of tert-butyl4-[(trifluoromethane)sulfonyloxy]-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.50 g, 1.36 mmol, (J. Med. Chem. 2014, 57, 2462),(3-amino-8-chloroisoquinolin-6-yl)boronic acid (602 mg, 2.71 mmol),Pd(dppf)Cl₂ (198 mg, 0.27 mmol) in 5:1 dioxane/water (12 mL) was addedK₃PO₄ (288 mg, 1.36 mmol) and NaOAc (167 mg, 2.04 mmol). The suspensionwas heated at 100° C. for 1 h. The reaction was concentrated in vacuo,and the resulting residue was purified by flash column chromatography(10:1 dichloromethane/methanol) to afford tert-butyl4-(3-amino-8-chloroisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.30 g, 56% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=397.1.

Step 2: tert-Butyl4-(8-chloro-3-cyclopropaneamidoisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl4-(3-amino-8-chloroisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.40 g, 1.0 mmol) in tetrahydrofuran (20 mL) was addedcyclopropanecarbonyl chloride (0.120 g, 1.15 mmol) and pyridine (0.20 g,2.5 mmol) at 25° C. After 3 h, the reaction was concentrated undervacuum to afford crude tert-butyl4-(8-chloro-3-cyclopropaneamidoisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.50 g) as a yellow solid. LCMS (ESI) [M+H]⁺=465.1.

Step 3: tert-Butyl4-(8-[[(tert-butoxy)carbonyl]amino]-3-cyclopropaneamidoisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate

A suspension of tert-butyl4-(8-chloro-3-cyclopropaneamidoisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.50 g, 1.08 mmol), tert-butyl N-[(tert-butoxy)carbonyl]carbamate (2.50g, 11.5 mmol), Pd₂(dba)₃ (0.20 g, 0.22 mmol), BrettPhos (0.20 g, 0.37mmol), and t-BuONa (0.260 g, 2.71 mmol) in dioxane (50 mL) was heated at90° C. After 1 h, the reaction was concentrated in vacuo, and theresulting residue was purified by flash column chromatography (10:1dichloromethane/methanol) to afford tert-butyl4-(8-[[(tert-butoxy)carbonyl]amino]-3-cyclopropaneamidoisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.40 g, 68% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=546.1.

Step 4:N-(8-Amino-6-[1H,2H,3H-pyrrolo[2,3-c]pyridin-4-yl]isoquinolin-3-yl)cyclopropanecarboxamide

To a solution of tert-butyl4-(8-[[(tert-butoxy)carbonyl]amino]-3-cyclopropaneamidoisoquinolin-6-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate(250 mg, 0.46 mmol) in dioxane (10 mL) was added concentratedhydrochloric acid (10 mL) at 25° C. After 30 min, the reaction wasconcentrated in vacuo, and the resulting residue was purified byPrep-HPLC to affordN-(8-amino-6-[1H,2H,3H-pyrrolo[2,3-c]pyridin-4-yl]isoquinolin-3-yl)cyclopropanecarboxamide(4.7 mg, 3%) as a yellow solid. ¹HNMR (300 MHz, DMSO-d₆) δ 10.80 (s,1H), 9.32 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.11-7.02(m, 1H), 6.73 (d, J=1.5 Hz, 1H), 6.36 (s, 2H), 6.18 (s, 1H), 3.55-3.50(m, 2H), 3.20-3.15 (m, 2H), 2.06-2.01 (m, 1H), 0.84-0.80 (m, 4H). LCMS(ESI): RT (min)=1.193, [M+H]+=346.1, Method=K.

Example 117(S)—N-(8-amino-6-(2-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(Compound 189) and(R)-N-(8-amino-6-(2-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide(Compound 190)

The title compound was prepared by following the procedure as describedforN-(8-amino-6-[1H,2H,3H-pyrrolo[2,3-c]pyridin-4-yl]isoquinolin-3-yl)cyclopropanecarboxamide(Compound 188) and making slight variations. The single isomers werepurified by chiral SFC. Compound 189: ¹H NMR (300 MHz, CD₃OD) δ 9.21 (s,1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.11 (s, 1H), 6.83 (s,1H), 4.18-3.91 (m, 1H), 3.34-3.31 (m, 1H), 2.81 (dd, J=16.8 Hz, 7.7 Hz,1H), 1.98-1.90 (m, 1H), 1.29 (d, J=6.2 Hz, 3H), 1.05-0.99 (m, 2H),0.98-0.85 (m, 2H). LCMS (ESI): RT (min)=1.09, [M+H]+=360.3, method=K.Compound 190: ¹NMR (300 MHz, CD₃OD) δ 9.21 (s, 1H), 8.28 (s, 1H), 7.94(s, 1H), 7.78 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 4.18-3.91 (m, 1H),3.34-3.31 (m, 1H), 2.81 (dd, J=16.8, 7.7 Hz, 1H), 1.98-1.90 (m, 1H),1.29 (d, J=6.2 Hz, 3H), 1.05-0.99 (m, 2H), 0.98-0.85 (m, 2H). LCMS(ESI): RT (min)=1.09, [M+H]+=360.3, Method=K.

Example 118(±)-(1S*,2S*,3R*)—N-(8-Amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropanecarboxamide(Compound 191) and(±)-(1S*,2S*,3S*)—N-(8-Amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropanecarboxamide(Compound 192)

Step 1:2-[(Benzyloxy)methyl]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide

To an ice-cooled solution of8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (282 mg, 1.05 mmol)in dichloromethane (30 mL) was sequentially added pyridine (6.0 mL, 74mmol), trans-2-[(benzyloxy)methyl]-3-methylcyclopropane-1-carboxylicacid (0.30 g, 1.4 mmol), and POCl₃ (321 mg, 2.09 mmol). The reactionmixture was warmed to 25° C. for 30 min before the addition of water (20mL). The resulting solution was extracted with dichloromethane (3×30mL). The combined organic was dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford2-[(benzyloxy)methyl]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(210 mg, 43%) as a yellow solid. LCMS (ESI) [M+H]⁺=472.0

Step 2: tert-ButylN-(3-[[2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A suspension oftrans-2-[(benzyloxy)methyl]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(420 mg, 0.89 mmol), NH₂Boc (2.61 g, 22 mmol), Pd₂(dba)₃. CHCl₃ (184 mg,0.18 mmol), Brettphos (191 mg, 0.36 mmol), and Cs₂CO₃ (1.16 g, 3.57mmol) in dioxane (10 mL) was heated at 120° C. After 1.5 h, the reactionwas concentrated in vacuo, and the resulting residue was purified byflash column chromatography (4:1 ethyl acetate/petroleum ether) toafford tert-butylN-(3-[[2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(450 mg, 92%) as a yellow solid. LCMS (ESI) [M+H]+=472.2.

Step 3: tert-Butyl3-(2-(hydroxymethyl)-3-methylcyclopropanecarboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A suspension of tert-butylN-(3-[[(1S,2S)-2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(350 mg, 0.63 mmol) and Pd(OH)₂ on carbon (2.5 g) in methanol (30 mL)was stirred for 30 min at 25° C. under H₂ (1 atm). The solids werefiltered, and the filtrated was concentrated in vacuo to afford crudetert-butylN-(3-[[(2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(0.20 g, 68%) as a light green solid. LCMS (ESI) [M+H]+=463.3.

Step 4:2-(8-(tert-Butoxycarbonylamino)-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)-3-methylcyclopropyl)methylmethanesulfonate

To an ice-cooled solution of tert-butylN-(3-[[(1S,2S)-2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(140 mg, 0.30 mmol) and triethylamine (183 mg, 1.81 mmol) indichloromethane (3 mL) was added MSCl (138 mg, 1.21 mmol) dropwise. Thereaction mixture warmed to 25° C. for 30 min before the addition ofwater (10 mL). The resulting solution was extracted with dichloromethane(50 mL). The organic extract was dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford crude2-(8-(tert-butoxycarbonylamino)-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)-3-methylcyclopropyl)methylmethanesulfonate (150 mg) as a yellow oil. LCMS (ESI) [M+H]+=541.3.

Step 5: tert-butylN-(3-[[2-(Cyanomethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A solution of tert-butylN-(3-[[2-(methanesulfonylmethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(0.10 g) and KCN (99 mg, 1.5 mmol) in DMSO (3 mL) was heated at 50° C.After 2 h, the reaction was diluted with water (20 mL). The resultingsolution was extracted with dichloromethane (50 mL). The collectedorganic was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. Purification by flash column chromatography (10:1dichloromethane/methanol) afforded tert-butylN-(3-[[2-(cyanomethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(0.070 g, 78%) as a brown solid. LCMS (ESI) [M+H]+=472.3.

Step 6:(±)-(1S*,2S*,3R*)—N-(8-Amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropanecarboxamideand(±)-(1S*,2S*,3S*)—N-(8-Amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropanecarboxamide

To a solution of tert-butylN-(3-[[2-(cyanomethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(0.070 g, 0.15 mmol) in dichloromethane (1 mL) was added trifluoroaceticacid (1.0 mL, 13 mmol) at 25° C. After 25 min, the reaction mixture wasadjusted to pH=8 with 2M aqueous sodium bicarbonate. The resultingsolution was extracted with dichloromethane (50 mL). The collectedorganic was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. Purification by Prep-HPLC afforded twodiastereoisomers. Compound 191: ¹HNMR (400 MHz, DMSO-d₆) 10.80 (s, 1H),9.32 (s, 1H), 8.67-8.39 (m, 2H), 8.26 (s, 1H), 7.45 (d, J=5.1 Hz, 1H),6.97-6.81 (m, 1H), 6.55 (d, J=1.5 Hz, 1H), 6.37 (s, 2H), 2.81 (dd,J=17.6, 7.3 Hz, 1H), 2.69 (dd, J=17.7, 7.7 Hz, 1H), 2.33 (s, 3H), 1.79(t, J=4.5 Hz, 1H), 1.71-1.57 (m, 1H), 1.52-1.37 (m, 1H), 1.17 (d, J=6.3Hz, 3H). LCMS (ESI) RT (min)=1.153, [M+H]+=372.2, Method=C. Compound192: ¹HNMR (400 MHz, DMSO-d₆) 10.79 (s, 1H), 9.32 (s, 1H), 8.48-8.36 (m,2H), 8.28 (s, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.99-6.86 (m, 1H), 6.55 (d,J=1.5 Hz, 1H), 6.34 (s, 2H), 2.83-2.61 (m, 2H), 2.30 (s, 3H), 2.15-2.03(m, 1H), 1.58-1.45 (m, 1H), 1.36 (dt, J=9.1, 6.1 Hz, 1H), 1.17 (d, J=6.1Hz, 3H). LCMS (ESI) RT (min)=1.924, [M+H]+=372.2 Method=C.

Example 119(2S)-2-(4-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 193) and(2R)-2-(4-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 194)

Step 1:2-(4-[[8-Chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-1H-pyrazol-1-yl)propanenitrile

A suspension of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (250 mg,0.86 mmol), 2-(4-bromo-1H-pyrazol-1-yl)propanenitrile (1.04 g, 5.21mmol), 3rd generation t-BuBrettPhos precatalyst (370 mg, 0.43 mmol),t-BuBrettPhos (210 mg, 0.43 mmol) and potassium carbonate (720 mg, 5.2mmol) in 1,4-dioxane (15 mL) was heated at 120° C. After 16 h, thereaction was concentrated in vacuo. Purification by flash columnchromatography (100% ethyl acetate) afforded2-(4-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-1H-pyrazol-1-yl)propanenitrile(240 mg, 68%) as a yellow oil. LCMS (ESI) [M+H]⁺=407.1.

Step 2: tert-Butyl N-(3-[[1-(1-cyanoethyl)-1H-pyrazol-4-yl]amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A suspension of2-(4-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-1H-pyrazol-1-yl)propanenitrile(0.420 g, 1.03 mmol), tert-butyl carbamate (3.63 g, 31.0 mmol),Pd₂(dba)₃. CHCl₃ (160 mg, 0.15 mmol), BrettPhos (110 mg, 0.20 mmol), andCs₂CO₃ (1.35 g, 4.12 mmol) in 1,4-dioxane (50 mL) was heated at 90° C.After 3 h, the reaction was concentrated in vacuo, and the resultingresidue was purified by flash column chromatography (95:5dichloromethane/methanol) to afford tert-butylN-(3-[[1-(1-cyanoethyl)-1H-pyrazol-4-yl]amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(0.40 g, 79%) as a brown oil. LCMS (ESI) [M+H]⁺=488.3.

Step 3:(2S)-2-(4-(8-Amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrileand(2R)-2-(4-(8-Amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile

To a solution of tert-butylN-(3-[[1-(1-cyanoethyl)-1H-pyrazol-4-yl]amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(350 mg, 0.71 mmol) in dichloromethane (10.0 mL) was addedtrifluoroacetic acid (10.0 mL, 134 mmol) at 25° C. After 1 h, thereaction was concentrated in vacuo. The residue was purified byPrep-HPLC followed by Chrial SFC to afford two enantiomers. Compound193:¹HNMIR (300 MHz, CD₃OD) δ 9.29 (s, 1H), 8.76 (s, 1H), 8.49 (d, J=5.0Hz, 1H), 8.41 (s, 1H), 8.09 (d, J=0.8 Hz, 1H), 7.62 (d, J=0.8 Hz, 1H),7.39-7.34 (m, 1H), 6.83 (s, 1H), 6.76 (d, J=6.1 Hz, 1H), 6.13 (s, 2H),5.82 (q, J=7.1 Hz, 1H), 2.22 (s, 3H), 1.80 (d, J=7.1 Hz, 3H). LCMS (ESI)RT (min)=1.08, [M+H]+=388.2. Method=K. Compound 194:¹HNMR (300 MHz,CD₃OD) δ 9.29 (s, 1H), 8.76 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.41 (s,1H), 8.09 (d, J=0.8 Hz, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.39-7.34 (m, 1H),6.83 (s, 1H), 6.76 (d, J=6.1 Hz, 1H), 6.13 (s, 2H), 5.82 (q, J=7.1 Hz,1H), 2.22 (s, 3H), 1.80 (d, J=7.1 Hz, 3H). LCMS (ESI) RT (min)=1.08,[M+H]+=388.2. Method=K.

Example 120(1R,2R,3R)—N-(8-Amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 195),(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 196),(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 197) and(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 198)

Step 1: Ethyldiphenylsulfonium tetrafluoroborate

To a solution of AgBF₄ (37.48 g, 192.5 mmol) in dichloromethane (450 mL)was added iodoethane (30.0 g, 192 mmol) under N₂ at room temperature.After 30 min, diphenylsulfide (107 g, 574 mmol) was added, and thereaction mixture was warmed to 35° C. After 16 h, the solids werefiltered out, and the filtrate was concentrated under vacuum. Theresulting residue was rinsed with dichloromethane/ether (3×500 mL) toafford ethyldiphenylsulfanium tetrafluoroboranuide (25 g, 39%) as anoff-white solid.

Step 2: tert-Butyl (2E)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-enoate

A solution of 4-iodo-1-methyl-1H-pyrazole (5.0 g, 24 mmol), tert-butylprop-2-enoate (9.23 g, 72.0 mmol), triethylamine (2.91 g, 28.8 mmol),Pd(OAc)₂ (538 mg, 2.40 mmol) and P(o-Tol)₃ (1.46 g, 4.80 mmol) inN,N-dimethylformamide (20 mL) was heated at 110° C. After 16 h, thereaction was concentrated under vacuum, and the resulting residue waspurified by flash column chromatography (3:1 petroleum ether/ethylacetate) to afford tert-butyl(2E)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-enoate as alight yellow oil (3.9g, 74%). LCMS (ESI): M+H⁺=209.0.

Step 3:tert-Butyl-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylate

To a solution of ethyldiphenylsulfonium tetrafluoroborate (6.53 g, 21.6mmol) in 1,2-dimethoxyethane (100 mL) and dichloromethane (15 mL) wasadded a solution of LDA (12.6 mL, 235.24 mmol, 2M in THF) dropwise at−78° C. After 30 min tert-butyl(2E)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-enoate (1.50 g, 7.20 mmol) in1,2-diemethoxyethane (10 mL) was added dropwise to the ylide solution at−78° C. After the addition, the reaction was warmed to room temperature.After 16 h, the reaction was diluted with water (100 mL), and theresulting mixture was extracted with chloroform (3×150 mL). Thecollected organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to afford crudetert-butyl-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylate(1.5 g) as a light yellow oil.

Step 4: 2-Methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylicacid

To a solution oftert-butyl-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylate(0.60 g, 2.5 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (10 mL) at room temperature. After 5 h, the reaction wasconcentrated under vacuum, and the resulting residue was diluted withwater (45 mL). The aqueous solution was basified to pH=9-10 with 10 Msodium hydroxide. The aqueous solution was then washed with ether (30mL), and the resulting aqueous was acidified to pH=3-4 with 1M aqueoushydrochloric acid. The acidic aqueous solution was extracted with ethylacetate (3×70 mL). The combined organic extracts were concentrated undervacuum to afford crude2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid asoff-white solid (450 mg, 70% purity, contains 30% TFA). LCMS (ESI):M-41⁺=181.0;

Step 5:N-[8-Chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

A mixture of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (1.0 g,3.5 mmol),2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid (690mg, 3.8 mmol), pyridine (7 mL), and propargyl alcohol (953 mg, 6.22mmol) in dichloromethane (50 mL) was stirred for 30 min at roomtemperature. The reaction mixture was diluted with water, and theresulting solution was extracted with dichloromethane. The organiclayers were combined and concentrated under vacuum. Purification byflash column chromatography (30:1 dichloromethane/methanol) affordedN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(750 mg, 48%) as a yellow solid. LCMS (ESI): M+H⁺=450.2

Step 6: tert-ButylN-(7-fluoro-3-[[2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(2.0 g, 4.45 mmol) in 1,4-dioxane (260 mL) was added tert-butylcarbamate (11.5 g, 98.2 mmol),tris(dibenylideneacetone)dipalladium-chloroform (691 mg, 0.67 mmol),dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine(477 mg, 0.89 mmol) and cesium carbonate (7.3 g, 22.41 mmol). Theresulting suspension was stirred heated at 90° C. After 2.5 h, thesolids were filtered, and the filtrate was concentrated under vacuum.The resulting residue was purified by flash column chromatography (15:1dichloromethane/methanol) to afford tert-butylN-(7-fluoro-3-[[2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1.2 g, 51%) as a yellow solid. LCMS (ESI): M+H⁺=531.1.

Step 7:(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide,(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide,(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamideand(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide

A solution ofN-(7-fluoro-3-[[2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1.0 g, 1.88 mmol) in dichloromethane (25 mL) and trifluoroacetic acid(25 mL) was stirred for 1.5 h at room temperature. The reaction wasconcentrated under vacuum. Purification by Prep-HPLC and chiral SFCafforded four isomers. Compound 195: ¹HNMIR (400 MHz, CD₃OD) δ 9.30 (s,1H), 8.47 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.45 (t, J=6.2Hz, 2H), 7.34 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.85 (s, 3H), 2.34-2.32(m, 4H), 2.17-2.14 (m, 1H), 1.62-1.48 (m, 1H), 1.35 (d, J=6.4 Hz, 3H).LCMS (ESI): RT (min)=1.14, [M+H]+=461.3, Method=K. Compound 196: ¹HNMR(400 MHz, CD₃OD) δ 9.31 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.41 (s, 1H),8.34 (s, 1H), 7.51 (s, 1H), 7.42 (d, J=5.2 Hz, 1H), 7.39 (s, 1H), 6.98(d, J=6.0 Hz, 1H), 3.88 (s, 3H), 2.52-2.49 (m, 1H), 2.30 (s, 3H),1.99-1.97 (m, 1H), 1.79-1.72 (m, 1H), 1.17 (d, J=6.4 Hz, 3H). LCMS(ESI): RT (min)=1.15, [M+H]+=461.3, Method=K. Compound 197: ¹HNMR (400MHz, CD₃OD) δ 9.31 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.41 (s, 1H), 8.34(s, 1H), 7.51 (s, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.39 (s, 1H), 6.98 (d,J=6.0 Hz, 1H), 3.88 (s, 3H), 2.53-2.49 (m, 1H), 2.31 (s, 3H), 1.99-1.97(m, 1H), 1.77-1.72 (m, 1H), 1.17 (d, J=6.4 Hz, 3H). LCMS (ESI): RT(min)=1.15, [M+H]+=461.3, Method=K.Compound 198:¹H NMR (400 MHz, CD₃OD)δ 9.30 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.45(t, J=6.2 Hz, 2H), 7.34 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.85 (s, 3H),2.34-2.32 (m, 4H), 2.17-2.14 (m, 1H), 1.67-1.61 (m, 1H), 1.35 (d, J=6.4Hz, 3H). LCMS (ESI): RT (min)=1.14, [M+H]+=461.3, Method=K.

Example 121(R)-2-(3-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 199 and(S)-2-(3-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 200)

The title compound was prepared using a procedure as described for(2S)-2-(4-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 193). The single isomers were isolated by chiral HPLC.Compound 199: ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.39 (d, J=4.4 Hz,2H), 7.80 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.89(s, 1H), 6.52 (s, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.59-5.54 (m, 1H), 2.39(s, 3H), 1.91 (d, J=6.8 Hz, 3H). LCMS (ESI): RT (min)=0.99,[M+H]+=461.3, Method=K. Compound 200: ¹HNMR (400 MHz,CD₃OD) δ 9.14 (s,1H), 8.39 (d, J=4.4 Hz, 2H), 7.80 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.40(d, J=5.2 Hz, 1H), 6.89 (s, 1H), 6.52 (s, 1H), 6.25 (d, J=2.4 Hz, 1H),5.59-5.54 (m, 1H), 2.39 (s, 3H), 1.91 (d, J=6.8 Hz, 3H). LCMS (ESI): RT(min)=0.99, [M+H]+=461.3, Method=K.

Example 122(S)-2-(4-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 201) and(R)-2-(4-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 202)

The title compound was prepared by following the procedure as describedfor(2S)-2-(4-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 193) and making slight variations. The enantiomers wereisolated by chiral HPLC. Compound 201: ¹HNMR (300 MHz, CD₃OD) δ 9.12 (s,1H), 8.39-8.37 (m, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 7.37(d, J=5.1 Hz,1H), 6.82 (d, J=5.1 Hz, 2H), 6.45 (s, 1H), 5.62 (q, J=7.2 Hz, 1H), 2.37(s, 3H), 1.90 (d, J=7.2 Hz, 3H). LCMS (ESI): RT (min)=1.585,[M+H]+=370.2, method=K. Compound 202: ¹HNMR (300 MHz, CD₃OD) δ 9.12 (s,1H), 8.39-8.37 (m, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 7.37(d, J=5.1 Hz,1H), 6.82 (d, J=5.1 Hz, 2H), 6.45 (s, 1H), 5.62 (q, J=7.2 Hz, 1H), 2.37(s, 3H), 1.90 (d, J=7.2 Hz, 3H). LCMS (ESI): RT (min)=0.946,[M+H]+=370.2, Method=K.

Example 1232-(4-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 203),2-(4-(8-amino-5,7-dichloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 204),(2S)-2-(4-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 205), and(2R)-2-(4-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-1H-pyrazol-1-yl)propanenitrile(Compound 206)

A solution of2-(4-[[8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-1H-pyrazol-1-yl)propanenitrile(0.20 g, 0.54 mmol) and NCS (72 mg, 0.54 mmol) in CH₃CN (10 mL) washeated at 50° C. After 2 h, the reaction was concentrated in vacuo, andthe resulting residue was sequentially purified by Prep-HPLC and ChiralSFC to afford four isomers. Compound 203: ¹HNMR (300 MHz, CD₃OD) δ 9.17(s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.69 (s,1H), 7.40 (d, J=5.1 Hz, 1H), 7.15 (s, 1H), 6.32 (s, 1H), 5.63 (q, J=7.2,1H), 2.22 (s, 3H), 1.89 (d, J=7.2, 3H). LCMS (ESI): RT(min)=1.12,[M+H]+=404.2, Method=K. Compound 204: ¹HNMR (300 MHz, CD₃OD) δ 9.26 (s,1H), 8.48 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 8.14 (1H, s), 7.70 (s, 1H),7.46 (d, J=5.1 Hz, 1H), 7.16 (s, 1H), 5.65 (q, J=7.2 Hz, 1H), 2.17 (s,3H), 1.90 (d, J=7.2 Hz, 3H). LCMS (ESI): RT(min)=2.20, [M+H]+=438.1,Method=K. Compound 205: ¹HNMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.42 (d,J=5.1 Hz, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.39 (d, J=5.1Hz, 1H), 6.80 (s, 2H), 5.61 (q, J=7.2 Hz, 1H), 2.22 (s, 3H), 1.89 (d,J=7.2 Hz, 3H). LCMS (ESI): RT(min)=1.78, [M+H]+=404.2, Method=K.Compound 206: ¹HNMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.42 (d, J=5.1 Hz,1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.39 (d, J=5.1 Hz, 1H),6.80 (s, 2H), 5.61 (q, J=7.2 Hz, 1H), 2.22 (s, 3H), 1.89 (d, J=7.2 Hz,3H). LCMS (ESI): RT (min)=1.78, [M+H]+=404.2, Method=K.

Example 124(1S,2S)—N-(8-amino-6-(4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 207) and(1R,2R)—N-(8-amino-6-(4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 208)

Step 1: 3-iodo-4-methyl-2-(pyrrolidin-1-yl)pyridine

A solution of 2-chloro-3-iodo-4-methylpyridine (600 mg, 2.367 mmol),pyrrolidine (336.71 mg, 4.73 mmol) and DIEA (611.88 mg, 4.73 mmol) inDMA (10.00 mL) was heated at 120° C. After 2 h, the reaction was dilutedwith water (50 mL). The resulting solution was extracted with ethylacetate (2×50 mL). The collected organic was dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to afford crude3-iodo-4-methyl-2-(pyrrolidin-1-yl)pyridine (630 mg, 92%) as a dark redoil. LCMS (ESI): M+H⁺=289.0.

Step 2:8-chloro-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-3-amine

A suspension of (3-amino-8-chloroisoquinolin-6-yl)boronic acid (926.4mg, 4.17 mmol), 3-iodo-4-methyl-2-(pyrrolidin-1-yl)pyridine (600 mg,2.08 mmol), XPhos palladium(II) biphenyl-2-amine chloride (328 mg, 0.42mmol), X-Phos (397 mg, 0.83 mmol), and potassium carbonate (576 mg, 4.16mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was heated at 100° C.After 2 h, the solids were filtered, and the filtrate was concentratedin vacuo. Purification by flash column chromatography (1:1 ethylacetate/petroleum ether) afforded8-chloro-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-3-amine(0.40 g, 57%) as a light yellow solid. LCMS (ESI): M+H⁺=339.1

Step 3:(±)-trans-N-[8-chloro-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

To an ice-cooled solution of8-chloro-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-3-amine(440 mg, 1.3 mmol),trans-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid (180mg, 1.08 mmol), and pyridine (6.00 mL, 74.54 mmol) in dichloromethane(40 mL) was added POC13 (249 mg, 1.63 mmol) dropwise. The reactionmixture was warmed to room temperature for 30 min and diluted with water(50 mL). The resulting solution was extracted with dichloromethane (100mL). The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford crude(±)-trans-N-[8-chloro-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(0.40 g, 76%) as a orange solid. LCMS (ESI): M+H⁺=487.0

Step 4: (±)-trans-tert-butylN-(3-[[2-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-8-yl)carbamate

A mixture of(±)-trans-N-[8-chloro-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(0.30 g, 0.62 mmol), tert-butyl carbamate (1.50 g, 12.8 mmol),Pd₂(dba)₃CHCl₃ (148 mg, 0.14 mmol), BrettPhos (120 mg, 0.22 mmol), andt-BuONa (152 mg, 1.58 mmol) in 1,4-dioxane (10 mL) was heated at 100° C.After 4 h, the reaction was concentrated in vacuo, and the resultingresidue was purified by flash column chromatography (10% ethyl acetatein petroleum ether→100% ethyl acetate) to afford crude(±)-trans-tert-butylN-(3-[[2-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-8-yl)carbamate(0.20 g, 57%) as a light yellow solid. LCMS (ESI): M+H⁺=568.0.

Step 5:(1S,2S)—N-(8-amino-6-(4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamideand(1R,2R)—N-(8-amino-6-(4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide

A solution of (±)-trans-tert-butylN-(3-[[2-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]-6-[4-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]isoquinolin-8-yl)carbamate(0.050 g, 0.088 mmol) in 4N HCl/1,4-dioxane (5 mL) was stirred for 24 hat room temperature. The reaction was concentrated in vacuo and theresulting residue was purified by chiral SFC to afford two enantiomers.Compound 207: ¹HNMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.24 (s, 1H), 7.93(d, J=5.2 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.67-6.60(m, 2H), 3.86 (s, 3H), 3.15-3.07 (m, 4H), 2.42-2.32 (m, 1H), 2.15-2.04(m, 4H), 1.75-1.67 (m, 4H), 1.57 (dt, J=9.1, 4.5 Hz, 1H), 1.33-1.20 (m,1H). LCMS (ESI): RT(min)=1.14, [M+H]+=467.0, Method=K. Compound 208:¹HNMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.24 (s, 1H), 7.93 (d, J=5.3 Hz,1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.67-6.60 (m, 2H), 3.86(s, 3H), 3.15-3.07 (m, 4H), 2.37 (dt, J=9.7, 4.4 Hz, 1H), 2.14-2.04 (m,4H), 1.75-1.67 (m, 4H), 1.57 (dt, J=9.3, 4.6 Hz, 1H), 1.33-1.20 (m, 1H).LCMS (ESI): RT(min)=1.38, [M+H]+=467.0, Method=K.

Example 125(±)-trans-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-chloroisoquinolin-3-yl)-2-(cyanomethyl)cyclopropanecarboxamide(Compound 209)

Step 1: tert-ButylN-[5-(3-amino-8-chloroisoquinolin-6-yl)-4-methylpyridin-3-yl]-N-[(tert-butoxy)carbonyl]carbamate

A suspension of 6-bromo-8-chloroisoquinolin-3-amine (5.8 g, 22 mmol),(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)boronic acid(16.0 g, 45.4 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (3.3 g, 4.0 mmol), and sodiumcarbonate (4.81 g, 45.38 mmol) in dioxane (100 mL) and water (10 mL) washeated at 85° C. After 16 h, the reaction was filtered, and the filtratewas concentrated in vacuo. Purification by flash column chromatography(1%→50% ethyl acetate/petroleum ether) afforded tert-butylN-[5-(3-amino-8-chloroisoquinolin-6-yl)-4-methylpyridin-3-yl]-N-[(tert-butoxy)carbonyl]carbamate(4.5 g, 41%) as a light yellow solid. LCMS (ESI): M+H⁺=485, 487.

Step 2: tert-butylN-[3-amino-6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate

A suspension of tert-butylN-[5-(3-amino-8-chloroisoquinolin-6-yl)-4-methylpyridin-3-yl]-N-[(tert-butoxy)carbonyl]carbamate(5.0 g, 10.3 mmol), tert-butyl carbamate (24 g, 205 mmol), BrettPhos(1.1 g, 2.05 mmol), Pd₂(dba)₃-CHCl₃ (2.13 g, 2.06 mmol), and Cs₂CO₃ (6.7g, 20.6 mmol) in 1,4-dioxane (120 mL) was heated at 85° C. After 3 h,the reaction was concentrated in vacuo, and the resulting residue waspurified by flash column chromatography (1%→10%dichloromethane/methanol) to afford tert-butylN-[3-amino-6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(1.5 g, 26%) as a light yellow solid. LCMS (ESI): M+H⁺=566.0

Step 3: (±)-trans-tert-butylN-[6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)-3-[[2-(cyanomethyl)cyclopropane]amido]isoquinolin-8-yl]carbamate

To an ice-cooled of solution oftrans-2-(cyanomethyl)cyclopropane-1-carboxylic acid (0.50 g, 3.40 mmol),tert-butylN-[3-amino-6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(132 mg, 0.23 mmol) and pyridine (4 mL, 50 mmol) in dichloromethane (20mL) was added POCl₃ (401 mg, 2.62 mmol) dropwise. The reaction waswarmed to room temperature for 1 h and then diluted with water (20 mL).The resulting solution was extracted with ethyl acetate (3×50 mL). Thecombine organics were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. Purification by flash column chromatography(1%→10% dichloromethane/methanol) afforded (±)-trans-tert-butylN-[6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)-3-[[2-(cyanomethyl)cyclopropane]amido]isoquinolin-8-yl]carbamate(330 mg, 12%) as a light yellow solid. LCMS (ESI): M+H⁺=673.1

Step 4:(±)-trans-N-[8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(cyanomethyl)cyclopropane-1-carboxamide

To a solution of trans-tert-butylN-[6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)-3-[[2-(cyanomethyl)cyclopropane]amido]isoquinolin-8-yl]carbamate(0.060 g, 0.089 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (5 mL) at room temperature. After 2 h, the reactionmixture was concentrated in vacuo to afford crudetrans-N-[8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(cyanomethyl)cyclopropane-1-carboxamide(20.4 mg, 31%) as a light yellow solid. LCMS (ESI): M+H⁺=473.1

Step 5:(±)-trans-N-[8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-chloroisoquinolin-3-yl]-2-(cyanomethyl)cyclopropane-1-carboxamide

A solution of(±)-trans-N-[8-amino-6-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(cyanomethyl)cyclopropane-1-carboxamide(110 mg, 0.30 mmol) and NCS (39.5 mg, 0.30 mmol) in CH₃CN (10 mL) washeated at 60° C. After 6 h, the reaction mixture was concentrated invacuo, and the resulting residue was purified by Prep-HPLC to afford(±)-trans-N-[8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-chloroisoquinolin-3-yl]-2-(cyanomethyl)cyclopropane-1-carboxamide(20.4 mg, 17%) as a light yellow solid.¹HNMR (400 MHz, DMSO-d₆) δ 10.95(s, 1H), 9.45 (s, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 6.88(s, 1H), 6.54 (s, 2H), 5.22 (s, 2H), 2.77-2.70 (m, 2H), 2.11-2.07 (m,1H), 1.82 (s, 3H), 1.58-1.55 (m, 1H), 1.15-1.08 (m, 1H), 0.99-0.92 (m,1H). LCMS (ESI): RT(min)=1.21, [M+H]+=407.0, method=M.

Example 126(1R,2R)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 210) and(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 211)

The title compound was prepared by following the procedure as describedfor(1S,2S)-N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 180) and making slight variations. The enantiomers wereisolated by chiral SFC. Compound 210: ¹HNMR (400 MHz, CD₃OD) δ 9.28 (s,1H), 8.41 (d, J=5.1 Hz, 1H), 8.26 (s, 1H), 7.51 (s, 1H), 7.37 (d, J=8.0Hz, 2H), 7.27 (d, J=5.1 Hz, 1H), 7.16 (s, 1H), 6.89 (s, 1H), 6.53 (d,J=1.4 Hz, 1H), 3.86 (s, 3H), 3.71 (s, 3H), 2.36 (ddd, J=9.6, 6.3, 4.0Hz, 1H), 2.18 (s, 3H), 2.14-2.05 (m, 1H), 1.56 (dt, J=9.1, 4.6 Hz, 1H),1.27-1.20 (m, 1H). LCMS (ESI): RT(min)=1.09, [M+H]⁺=479.3, Method=K.Compound 211: ¹HNMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 8.41 (d, J=5.1 Hz,1H), 8.26 (s, 1H), 7.51 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.27 (d, J=5.1Hz, 1H), 7.16 (s, 1H), 6.89 (s, 1H), 6.53 (d, J=1.4 Hz, 1H), 3.86 (s,3H), 3.71 (s, 3H), 2.36 (ddd, J=9.8, 6.4, 4.0 Hz, 1H), 2.18 (s, 3H),2.14-2.07 (m, 1H), 1.56 (dt, J=9.2, 4.6 Hz, 1H), 1.28-1.19 (m, 1H) LCMS(ESI): RT(min)=1.09, [M+H]⁺=479.3, Method=K.

Example 127(1S,2S,3S)—N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 212),(1S,2R,3S)—N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 213),(1R,2S,3R)—N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 214), and(1R,2R,3R)—N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 215)

The title compound was prepared by following the procedure as describedfor(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 195) and making slight variations. The isomers were isolatedby chiral SFC. Compound 212:¹HNMR (300 MHz, CD₃OD) δ 9.26 (s, 1H),8.45-8.43 (m, 2H), 8.34 (s, 1H), 7.48 (s, 1H), 7.45 (d, J=6.0 Hz 1H),7.35 (s, 1H), 7.03 (s, 1H), 6.70 (d, J=3.0 Hz, 1H), 3.86 (s, 3H), 2.41(s, 3H), 2.34 (dd, J=6.5, 4.8 Hz, 1H), 2.17 (dd, J=9.1, 4.9 Hz, 1H),1.66 (dt, J=8.9, 6.2 Hz, 1H), 1.37 (d, J=6.2 Hz, 3H). LCMS (ESI):RT(min)=0.95, [M+H]⁺=413.4, Method=N. Compound 213: ¹HNMR (400 MHz,CD₃OD) δ 9.26 (s, 1H), 8.46-8.37 (m, 2H), 8.32 (s, 1H), 7.52 (s, 1H),7.41 (d, J=4.8 Hz, 2H), 7.04 (s, 1H), 6.69 (d, J=3.0 Hz, 1H), 3.89 (s,3H), 2.52 (dd, J=9.3, 4.7 Hz, 1H), 2.39 (s, 3H), 1.99 (t, J=4.7 Hz, 1H),1.82-1.72 (m, 1H), 1.07 (d, J=6.3 Hz, 3H). LCMS (ESI): RT(min)=0.75,[M+H]⁺=413.2, Method=K. Compound 214:¹HNMR (300 MHz, CD₃OD) δ 9.24 (s,1H), 8.42 (d, J=5.4 Hz, 2H), 8.33 (s, 1H), 7.53 (s, 1H), 7.41 (t, J=2.6Hz, 2H), 7.01 (s, 1H), 6.70 (d, J=3.0 Hz, 1H), 3.90 (s, 3H), 2.53 (dd,J=9.2, 4.7 Hz, 1H), 2.39 (s, 3H), 2.00 (t, J=4.7 Hz, 1H), 1.77 (ddd,J=9.4, 6.1, 4.7 Hz, 1H), 1.07 (d, J=6.2 Hz, 3H). LCMS (ESI):RT(min)=0.74, [M+H]+=413.3, Method=K. Compound 215: ¹HNMR (300 MHz,CD₃OD) δ 9.31 (s, 1H), 8.49-8.39 (m, 2H), 8.34 (s, 1H), 7.55-7.41 (m,2H), 7.35 (s, 1H), 7.03 (s, 1H), 6.70 (d, J=3.0 Hz, 1H), 3.86 (s, 3H),2.41 (s, 3H), 2.34 (dd, J=6.5, 4.9Hz, 1H), 2.17 (dd, J=9.1, 4.9 Hz, 1H),1.66 (dt, J=9.0, 6.3 Hz, 1H), 1.37 (d, J=6.2 Hz, 3H). LCMS (ESI):RT(min)=0.95, [M+H]+=413.3, Method=N.

Example 128(1R,2R)—N-(8-amino-6-(2,6-dichlorophenyl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 216) and(1S,2S)—N-(8-amino-6-(2,6-dichlorophenyl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 217)

The title compound was prepared by following the procedure as describedfor(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 123) and making slight variations. The enantiomers wereisolated by chiral SFC. Compound 216: ¹HNMR (400 MHz, DMSO-d₆) δ 10.78(s, 1H), 9.32 (s, 1H), 8.26 (s, 1H), 7.63-7.55 (m, 3H), 7.48-7.41 (m,1H), 7.29 (s, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 6.35 (s, 2H), 3.77 (s,3H), 2.21-2.16 (m, 2H), 1.39-1.35 (m, 1H), 1.19-1.14 (m, 1H). LCMS(ESI): RT(min)=1.30, [M+H]+=452.1, Method=K. Compound 217: ¹HNMR (400MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.32 (s, 1H), 8.26 (s, 1H), 7.65-7.51 (m,3H), 7.46 (dd, J=8.7, 7.5 Hz, 1H), 7.30 (s, 1H), 6.79 (s, 1H), 6.40 (s,1H), 6.35 (s, 2H), 3.78 (s, 3H), 2.23-2.13 (m, 2H), 1.42-1.33 (m, 1H),1.21-1.12 (m, 1H). LCMS (ESI): RT(min)=1.31, [M+H]⁺=452.2, Method=K.

Example 129(1S,2S)—N-(8-amino-6-(2,6-difluorophenyl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 218) and(1R,2R)—N-(8-amino-6-(2,6-difluorophenyl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 219)

The title compound was prepared by following the procedure as describedfor(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 123) and making slight variations. The single isomers wereisolated by chiral SFC. Compound 218: ¹HNMR (400 MHz, CD₃OD) δ 9.24 (s,1H), 8.30 (s, 1H), 7.51 (s, 1H), 7.44 (ddd, J=8.5, 6.3, 2.1 Hz, 1H),7.38 (s, 1H), 7.10 (t, J=8.0 Hz, 3H), 6.78 (s, 1H), 3.86 (s, 3H), 2.37(td, J=6.1, 3.2 Hz, 1H), 2.11 (dt, J=8.7, 4.7 Hz, 1H), 1.57 (ddd, J=9.2,5.1, 4.1 Hz, 1H), 1.26 (ddd, J=8.2, 6.4, 4.1 Hz, 1H). LCMS (ESI):RT(min)=1.49, [M+H]⁺=420.2, Method=K. Compound 219: ¹HNMR (400 MHz,CD₃OD) δ 9.24 (s, 1H), 8.30 (s, 1H), 7.51 (s, 1H), 7.44 (ddd, J=8.5,6.3, 2.1 Hz, 1H), 7.38 (s, 1H), 7.10 (t, J=8.0 Hz, 3H), 6.78 (s, 1H),3.86 (s, 3H), 2.37 (td, J=6.1, 3.2 Hz, 1H), 2.11 (dt, J=8.7, 4.7 Hz,1H), 1.57 (ddd, J=9.2, 5.1, 4.1 Hz, 1H), 1.26 (ddd, J=8.2, 6.4, 4.1 Hz,1H). LCMS (ESI): RT(min)=1.49, [M+H]⁺=420.2, Method=K.

Example 130(1S,2S)—N-(8-amino-6-(2-cyano-6-methylphenyl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 220) and(1R,2R)—N-(8-amino-6-(2-cyano-6-methylphenyl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 221)

The title compound was prepared by following the procedure as describedfor(±)-trans-N-(8-amino-6-(8-methylpyrido[3,2-b]pyrazin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropanecarboxamide(Compound 123) and making slight variations. The enantiomers wereisolated by chiral SFC. Compound 220: ¹HNMR (300 MHz, DMSO-d₆) δ 11.14(s, 1H), 9.37 (s, 1H), 8.24 (s, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.66 (d,J=5.5 Hz, 1H), 7.50 (t, J=5.8 Hz, 1H), 6.86 (s, 1H), 6.46 (d, J=7.2 Hz,3H), 2.78-2.72 (m, 1H), 2.16-2.10 (m, 4H), 1.62-1.57 (m, 1H), 1.45-1.43(m, 1H). LCMS (ESI): RT(min)=1.55, [M+H]⁺=368.2, Method=M. Compound 221:¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.37 (s, 1H), 8.24 (s, 1H),7.76 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.5 Hz, 1H), 7.50 (t, J=5.8 Hz, 1H),6.86 (s, 1H), 6.46 (d, J=7.2 Hz, 3H), 2.78-2.72 (m, 1H), 2.16-2.10 (m,4H), 1.62-1.57 (m, 1H), 1.45-1.43 (m, 1H). LCMS (ESI): RT(min)=1.55,[M+H]⁺=368.2, Method=M.

Example 131(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 222) and(1R,2R)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 223)

The title compound was prepared by following the procedure as describedfor(1S,2S)—N-(8-amino-6-(4-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound 180) and making slight variations. The enantiomers wereisolated by chiral SFC. Compound 222: ¹HNMR (400 MHz, DMSO-d₆) 10.74 (s,1H), 9.27 (s, 1H), 8.48 (d, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.56 (s, 1H),7.38-7.29 (m, 3H), 6.71 (s, 1H), 6.33 (s, 1H), 6.20 (s, 2H), 5.77 (s,1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.18 (t, J=6.0 Hz, 2H), 2.09 (s, 3H),1.35-1.34 (m, 1H), 1.17-1.15 (m, 1H). LCMS (ESI): RT(min)=1.10,[M+H]⁺=479.3, Method=K. Compound 223: ¹HNMR (400 MHz, DMSO-d₆) 10.74 (s,1H), 9.27 (s, 1H), 8.48 (d, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.56 (s, 1H),7.38-7.29 (m, 3H), 6.71 (s, 1H), 6.33 (s, 1H), 6.20 (s, 2H), 5.77 (s,1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.18 (t, J=6.0 Hz, 2H), 2.09 (s, 3H),1.35-1.34 (m, 1H), 1.17-1.15 (m, 1H). LCMS (ESI): RT(min)=1.10,[M+H]⁺=479.3, Method=K.

Example 132exo-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo[3.1.0]hexane-6-carboxamide(Compound 224),exo-N-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo[3.1.0]hexane-6-carboxamide(Compound 225) andexo-N-(8-amino-5,7-dichloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo[3.1.0]hexane-6-carboxamide(Compound 226)

Step 1:(exo)-3-[(tert-butyldiphenylsilyl)oxy]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-1-methylbicyclo[3.1.0]hexane-6-carboxamide

To an ice-cooled solution of(exo)-3-[(tert-butyldiphenylsilyl)oxy]bicyclo[3.1.0]hexane-6-carboxylicacid (289 mg, 0.75 mmol) (WO2015091889),8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (488 mg, 1.80 mmol)and pyridine (1 mL) in dichloromethane (5 mL) was added POCl₃ (491 mg,3.20 mmol) dropwise. The reaction was warmed to room temperature for 30min and then diluted with water (10 mL). The solution was extracted withethyl acetate (3×50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo.Purification by flash column chromatography (1:1 ethyl acetate/petroleumether) afforded(exo)-3-[(tert-butyldiphenylsilyl)oxy]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-1-methylbicyclo[3.1.0]hexane-6-carboxamide(0.30 g, 61%) as light yellow oil. LCMS (ESI): M+H⁺=632.2

Step 2: Tert-butylN-[6-(4-methylpyridin-3-yl)-3-[(exo)-3-[(tert-butyldiphenylsilyl)oxy]bicyclo[3.1.0]hexane-6-amido]isoquinolin-8-yl]carbamate

A suspension of(exo)-3-[(tert-butyldiphenylsilyl)oxy]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]bicyclo[3.1.0]hexane-6-carboxamide(0.40 g, 0.63 mmol), tert-butyl carbamate (1.85 mg, 0.02 mmol),Pd₂(dba)₃ (130 mg, 0.14 mmol), Cs₂CO₃ (819 mg, 2.51 mmol), and BrettPhos(135 mg, 0.25 mmol) in dioxane (10 mL) was heated at 120° C. After 2 h,the reaction was filtered, and the filtrate was concentrated in vacuo.Purification by flash column chromatography (1:1 ethyl acetate/petroleumether) afforded tert-butylN-[6-(4-methylpyridin-3-yl)-3-[(exo)-3-[(tert-butyldiphenylsilyl)oxy]bicyclo[3.1.0]hexane-6-amido]isoquinolin-8-yl]carbamate(315 mg, 70%) as a yellow solid. LCMS (ESI): M+H⁺=713.3

Step 3:(exo)-N-[8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-[(tert-butyldiphenylsilyl)methyl]bicyclo[3.1.0]hexane-6-carboxamide

A solution of tert-butylN-[6-(4-methylpyridin-3-yl)-3-[(exo)-3-[(tert-butyldiphenylsilyl)methyl]bicyclo[3.1.0]hexane-6-amido]isoquinolin-8-yl]carbamate(630 mg, 0.88 mmol) in trifluoroacetic acid (6 mL) and dichloromethane(30 mL) was stirred for 1 h at room temperature. The reaction wasconcentrated in vacuo, and the residue was diluted with DCM (20 mL). Themixture was basified to pH=8 with a solution of NH₃ in methanol (7 M)and concentrated. Purification by flash column chromatography provided(exo)-N-[8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-[(tert-butyldiphenylsilyl)methyl]bicyclo[3.1.0]hexane-6-carboxamide(480 mg, 89%) as a yellow solid. LCMS (ESI): M+H⁺=613.3

Step 4:(exo)-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butyldiphenylsilyloxy)bicyclo[3.1.0]hexane-6-carboxamide,(exo)-N-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butydiphenylsilyoxy)bicycle[3.1.0]hxane-6-carboxamideand(exo)-N-(8-amino-5,7-dichloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butyldiphenylsilyloxy)bicyclo[3.1.0]hexane-6-carboxamide

A solution of(exo)-N-[8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-[(tert-butyldiphenylsilyl)methyl]bicyclo[3.1.0]hexane-6-carboxamide(320 mg, 0.52 mmol) and NCS (35 mg, 0.52 mmol) in CH₃CN (10 mL) washeated at 50° C. After 1 h, additional NCS (35 mg, 0.52 mmol) was added,and the solution was maintained at 50° C. for another 2 h. The reactionwas concentrated under vacuum, and the resulting residue was purified byflash column chromatography (10:1 dichloromethane/methanol) to provide amixture of(exo)-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butyldiphenylsilyloxy)bicyclo[3.1.0]hexane-6-carboxamide,(exo)-N-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butydiphenylsilyoxy)bicycle[3.1.0]hxane-6-carboxamideand(exo)-N-(8-amino-5,7-dichloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butyldiphenylsilyloxy)bicyclo[3.1.0]hexane-6-carboxamide(0.30 g, 89%) as a solid. LCMS (ESI): M+H⁺=647.3, 681.2;

Step 5:(exo)-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo[3.1.0]hexane-6-carboxamideand(exo)-N-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo[3.1.0]hexane-6-carboxamideand(exo)-N-(8-amino-5,7-dichloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-hydroxybicyclo[3.1.0]hexane-6-carboxamide

To a mixture of(exo)-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butyldiphenylsilyloxy)bicyclo[3.1.0]hexane-6-carboxamide,(exo)-N-(8-amino-5-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butydiphenylsilyoxy)bicycle[3.1.0]hxane-6-carboxamideand(exo)-N-(8-amino-5,7-dichloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(tert-butyldiphenylsilyloxy)bicyclo[3.1.0]hexane-6-carboxamide(0.30 g) in tetrahydrofuran (10 mL) was added TBAF (1.03 g, 3.93 mmol)at room temperature. After 30 min the reaction was concentrated invacuo, and the crude product was purified by Prep-HPLC to afford threeproducts. Compound 224: ¹HNMR (300 MHz, DMSO-d₆) 10.59 (s, 1H), 9.44 (s,1H), 8.49 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.37 (d, J=6.0Hz, 1H), 6.91 (s, 1H), 6.57 (s, 2H), 4.70 (d, J=6.0 Hz, 1H), 3.85-3.78(m, 1H), 2.11 (s, 3H), 2.09-2.04 (m, 2H), 1.89-1.87 (m, 1H), 1.73-1.71(m, 2H), 1.69-1.61 (m, 2H). LCMS (ESI): RT(min)=2.236, [M+H]+=409.1,Method=K. Compound 225: ¹HNMR (300 MHz, DMSO-d₆) 10.70 (s, 1H), 9.37 (s,1H), 8.62 (s, 1H), 8.49 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.38 (d, J=6.0Hz, 1H), 6.54 (s, 2H), 6.44 (s, 1H), 4.71 (d, J=6.0 Hz, 1H), 3.83-3.78(m, 1H), 2.12 (s, 3H), 2.09-2.05 (m, 2H), 1.92-1.90 (m, 1H), 1.76-1.74(m, 2H), 1.69-1.62 (m, 2H). LCMS (ESI): RT(min) =1.029, [M+H]+=409.2,Method=K. Compound 226: ¹HNMR (300 MHz, DMSO-d₆) 10.79 (s, 1H), 9.53 (s,1H), 8.64 (s, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.29 (s, 1H), 7.43 (d, J=6.0Hz, 1H), 6.77 (s, 2H), 4.71 (d, J=6.0 Hz, 1H), 3.85-3.79 (m, 1H),2.12-2.08 (m, 2H), 2.05 (s, 3H), 1.92-1.90 (m, 1H), 1.75-1.74 (m, 2H),1.69-1.62 (m, 2H). LCMS (ESI): RT(min)=1.205, [M+H]+=443.1, Method=L.

Example 1331-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(cyclopropylmethyl)urea(Compound 29)

Step 1: tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (1.14 g, 3.54mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(518.19 mg, 0.71 mmol), potassium carbonate (1.47 g, 10.62 mmol) andtert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (2.0 g, 5.32 mmol) in 1,4-dioxane (20mL)/water (4 mL) was stirred for 1 hour at 90° C. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with petroleum ether/ethylacetate (3/1) to afford tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1.5 g, 3.37 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=445.1.

Step 2: tert-butyl7-(8-chloro-7-fluoro-3-(((4-nitrophenoxy)carbonyl)amino)isoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(200 mg, 0.45 mmol), pyridine (106.68 mg, 1.35 mmol) and4-nitrophenylchloroformate (135.92 mg, 0.67 mmol) in dichloromethane (4mL) was stirred at room temperature for 2 hours. The resulting solutionwas directly used in the next step without work up. LCMS (ESI)[M+H]⁺=610.

Step 3: tert-butyl7-[8-chloro-3-(cyclopropylmethylcarbamoylamino)-7-fluoro-64soquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4] oxazine-1-carboxylate

To a solution of tert-butyl7-[8-chloro-7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylatewas added cyclopropanemethylamine (34.98 mg, 0.49 mmol) and pyridine(77.8 mg, 0.98 mmol). The reaction was stirred at 25° C. for 2 hours.The solvent was concentrated under vacuum. The residue was purified byreverse phase flash (C18 column, CH₃CN/H₂O=0-80% in 40 mins) to affordtert-butyl7-[8-chloro-3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(150 mg, 0.28 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=542.

Step 4: tert-butyl7-[8-(tert-butoxycarbonylamino)-3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of1-[8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-(cyclopropylmethyl)urea(150 mg, 0.28 mmol) and cesium carbonate (353.92 mg, 1.09 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (74.96 mg, 0.07mmol),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(77.74 mg, 0.14 mmol) in 1,4-dioxane (10 mL) was stirred at 90° C. for 3hours. After filtration, the solvent was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butyl7-[8-(tert-butoxycarbonylamino)-3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(130 mg, 0.21 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=623.

Step 5:1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-(cyclopropylmethyl)urea

A solution of tert-butyl7-[8-(tert-butoxycarbonylamino)-3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(130 mg, 0.21 mmol) and trifluoroacetic acid (2 mL) in dichloromethane(4 mL) was stirred at 25° C. for 1 hour. The solvent was concentratedunder vacuum. The residue was purified by prep-HPLC (XBridge Prep C18OBD Column 19×150 mm 5 um; Water (10 mmol/L sodium bicarbonate):CH₃CN=30% B to 50% B in 7 min; 25 mL/min) to afford1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-(cyclopropylmethyl)urea(49.8 mg, 0.12 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=423. ¹H NMR(300 MHz, Methanol-d₄) δ 9.21 (s, 1H), 7.53 (s, 1H), 7.35 (s, 1H), 6.86(d, J=6.2 Hz, 1H), 4.42-4.35 (m, 2H), 3.48 (t, J=4.4 Hz, 2H), 3.18 (d,J=6.9 Hz, 2H), 2.00 (d, J=1.7 Hz, 3H), 1.11-1.08 (m, 1H), 0.58-0.50 (m,2H), 0.29-0.27 (m, 2H).

Example 134(1R,2S,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 9);(1S,2R,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 10);(1S,2S,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 11) and(1R,2R,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 12)

Step 1: tert-butyl7-(8-chloro-3-((1S,3S)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1.6 g, 3.6 mmol) and2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid (908.09 mg,4.68 mmol) in dichloromethane (30 mL) and pyridine (6 mL) was stirred at0° C. for 3 minutes. Phosphorus oxychloride (1.1 g, 7.19 mmol) was addedat 0° C. and the mixture was stirred at 25° C. for 30 minutes. Theresulting solution was extracted with dichloromethane. The organiclayers were combined and concentrated to afford tert-butyl7-[8-chloro-3-[[(1S,2S)-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1.4 g, 2.25 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=621.

Step 2: tert-butyl7-(8-((tert-butoxycarbonyl)amino)-3-(2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

A mixture of tert-butyl7-[8-chloro-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1.4 g, 2.25 mmol),tert-butyl carbamate (6.6 g, 56.35 mmol),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (466.59 mg,0.45 mmol),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(483.27 mg, 0.90 mmol) and cesium carbonate (3.67 g, 11.27 mmol) in1,4-dioxane (80 mL) was stirred at 90° C. for 2 hours. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5) to afford tert-butyl7-[8-(tert-butoxycarbonylamino)-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1 g, 1.42 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=702.

Step 3:(1R,2S,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;(1S,2R,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;(1S,2S,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamideand(1R,2R,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

A solution of tert-butyl7-[8-(tert-butoxycarbonylamino)-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1.0 g, 1.42 mmol) and 2,2,2-trifluoroacetic acid (10 mL) indichloromethane (50 mL) was stirred at 25° C. for 1 hour. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH10 with NH₃. H₂O. The crude product was purified by Prep-HPLC with thefollowing conditions:Column:)(Bridge Prep OBD C18 Column 30×150mm 5 um;Mobile Phase A:Water (10 mmol/L sodium bicarbonate), Mobile Phase B:ACN; Flow rate: 60 mL/min; Gradient: 25% B to 47% B in 7 min; 254/220nm; Rt: 6.13 min to afford a mixture of isomers ofN-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxamide(400 mg, 0.80 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=502. Themixture was separated into 4 isomers by chiral SFC (Cyclopropanestereochemistry for isomers: pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; All absolute stereochemistryarbitrarily assigned): Compound 9: (28.7 mg, 0.057 mmol) as a yellowsolid. Retention time:2.401 min(CHIRALPAK IE-3, 0.46*10 cm; 3 μm;

-   MtBE(0.1% DEA):MeOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=502; ¹H    NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.38 (s, 1H), 8.30 (s, 1H),    7.52 (s, 1H), 7.33 (s, 1H), 7.25 (d, J=0.8 Hz, 1H), 6.85 (d, J=6.2    Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.30 (s, 2H), 3.77 (s, 3H),    3.37 (s, 2H), 2.26-2.17 (m, 2H), 1.93 (d, J=1.6 Hz, 3H), 1.86-1.43    (m, 3H), 0.92 (t, J=7.3 Hz, 1H). Compound 10: (22.5 mg, 0.045 mmol)    as a yellow solid. Retention time: 2.090 min (Repaired Chiral IA,    0.46*10 cm; 5 μm; MtBE(0.1% DEA):MeOH=70:30; 1.0 ml/min); LCMS (ESI)    [M+H]⁺=502; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.38 (s, 1H),    8.30 (s, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.25 (d, J=0.8 Hz, 1H),    6.85 (d, J=6.2 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.30 (s, 2H),    3.77 (s, 3H), 3.38 (s, 2H), 2.35-2.12 (m, 2H), 1.93 (d, J=1.6 Hz,    3H), 1.84-1.38 (m, 3H), 0.92 (t, J=7.3 Hz, 1H). Compound 12: (89.3    mg, 0.18 mmol) as a yellow solid. Retention time: 4.15 min (Repaired    Chiral IA, 0.46*10 cm; 5 μm;-   MtBE(0.1% DEA):MeOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=502; ¹H    NMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.40 (s, 1H), 8.28 (s, 1H),    7.53 (s, 1H), 7.33 (s, 1H), 7.29 (s, 1H), 6.84 (d, J=6.2 Hz, 1H),    6.21 (s, 2H), 5.67 (s, 1H), 4.29 (s, 2H), 3.80 (s, 3H), 3.37 (s,    2H), 2.37-2.29 (m, 1H), 2.17 (t, J=4.7 Hz, 1H), 1.93 (d, J=1.6 Hz,    3H), 1.58-1.44 (m, 1H), 1.30-1.16 (m, 2H), 0.89 (t, J=7.3 Hz, 3H).    Compound 11: (113.1 mg, 0.23 mmol) as a yellow solid. Retention    time: 2.66 min(CHIRALPAK IE-3, 0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):MeOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=502; ¹H    NMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.40 (s, 1H), 8.29 (s, 1H),    7.53 (s, 1H), 7.33 (s, 1H), 7.29 (s, 1H) 6.84 (d, J=6.2 Hz, 1H),    6.21 (s, 2H), 5.67 (s, 1H), 4.29 (s, 2H), 3.80 (s, 3H), 3.37 (s,    2H), 2.38-2.29 (m, 1H), 2.17 (t, J=4.7 Hz, 1H), 1.93 (d, J=1.6 Hz,    3H), 1.58-1.44 (m, 1H), 1.30-1.16 (m, 2H), 0.89 (t, J=7.3 Hz, 3H).

Example 135(1R,2S,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(assumed) (Compound 36),(1S,2R,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(assumed) (Compound 35),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(assumed) (Compound 34) and(1S,2S,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(assumed) (Compound 33)

Step 1: ethyldiphenylsulfanium tetrafluoroboranuide

To a solution of AgBF4 (37.48 g, 192.53 mmol) in dichloromethane (450mL) was added iodoethane (30 g, 192.35 mmol) under nitrogen. Thesolution was stirred for 30 minutes at room temperature.Phenylsulfanyl)benzene (106.92 g, 573.99 mmol) was added and thenstirred for 16 hours at 35° C. The mixture was filtered and the filtratewas concentrated under vacuum. The residue was washed withdichloromethane/ether (1/1) to afford ethyldiphenylsulfaniumtetrafluoroboranuide (25 g, 116.28 mmol) as off-white solid. LCMS (ESI)[M+H]⁺=215.

Step 2: trans-tert-butyl2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

To a solution of ethyl(diphenyl)sulfonium (1.55 g, 7.2 mmol) indichloromethane (2 mL) and 1,2-dimethoxyethane (20 mL) was added lithiumdiisopropylamide (4.2 mL, 8.4 mmol) at −78° C. The resulting solutionwas stirred for 1 hour at −78° C. tert-Butyl(E)-3-(1-methylpyrazol-4-yl)prop-2-enoate (500 mg, 2.4 mmol) was addedat −78° C. The mixture was stirred at 25° C. for 6 hours. The reactionwas quenched with water and then extracted with dichloromethane. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum to afford trans-tert-butyl2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (550 mg, crude)as a yellow oil. LCMS (ESI) [M+H]⁺=237.

Step 3: (+/−)-trans-tert-butyl2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

A solution of trans-tert-butyl2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (500 mg, crude)in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (4 mL) wasstirred at 25° C. for 2 hours. The solvent was concentrated undervacuum. The reaction mixture was adjusted to pH 7 with ammonia inmethanol (7 mol/L). The residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% HCl in water) to afford a mixtureof 4 stereoisomers of2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid wherepyrazole is trans to carboxylic acid (180 mg, 0.99 mmol) as a yellowoil. LCMS (ESI) [M+H]⁺=181.

Step 4: tert-butyl7-[8-chloro-7-fluoro-3-[[(1S)-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

To a solution oftrans-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid(182.27 mg, 1.01 mmol) in dichloromethane (15 mL) and pyridine (3 mL)was added tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(450 mg, 1.01 mmol) at 25° C. The resulting solution was stirred for 20minutes at 25° C. Phosphorus oxychloride (309.51 mg, 2.02 mmol) wasadded and stirred at 25° C. for 30 minutes. The reaction was quenchedwith water and then extracted with dichloromethane. The organic layerswere combined, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (9:1) to affordtert-butyl7-[8-chloro-7-fluoro-3-[[(1S)-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(320 mg, 0.53 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=607.

Step 5: tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[(1S)-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

To a solution of tert-butyl7-[8-chloro-7-fluoro-3-[[(1S)-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(420 mg, 0.69 mmol), tert-butyl carbamate (2.43 g, 20.76 mmol),tris(dibenzylideneacetone)dipalladium (143.21 mg, 0.14 mmol) andBrettphos (148.61 mg, 0.28 mmol) in 1,4-dioxane (15 mL) was added cesiumcarbonate (902.15 mg, 2.77 mmol) at 25° C. The resulting solution wasstirred at 90° C. for 3 hours. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol (9/1)to afford tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[(1S)-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(450 mg, 0.65 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=688.

Step 6:(1R,2S,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1S,2R,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1R,2R,3R)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamideand(1S,2S,3S)—N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

A solution of tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[(1S)-2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(800 mg, 1.16 mmol) in dichloromethane (10 mL) and 2,2,2-trifluoroaceticacid (10 mL) was stirred at 25° C. for 2 hours. The solvent wasconcentrated under vacuum. The crude product was purified by prep-HPLC(C18 silica gel; 0.5% sodium bicarbonate in water:ACN=20%-50% in 7 min)to afford the mixture (260 mg, 0.44 mmol) as a yellow solid. The mixturewas separated by chiral-HPLC to afford four isomers (Cyclopropanestereochemistry for each isomer: pyrazole trans to amide; methylrelative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned): Compound 33: (27.3 mg, 0.056mmol) as a yellow solid. Retention time: 3.92 min (CHIRALPAK IE-3.0.46*10 cm; 3 μm; MtBE(0.3%IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI)[M+H]⁺=488.2; ¹HNMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.39 (s, 1H),8.32 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 6.86 (d, J=6.2Hz, 1H), 6.21 (s, 2H), 5.68 (s, 1H), 4.30-4.29 (m, 2H), 3.77 (s, 3H),3.38-3.37(m, 2H), 2.28-2.12 (m, 2H), 1.94 (s, 3H), 1.64-1.50 (m, 1H),1.28 (d, J=6.1 Hz, 3H). Compound 34: (26.6 mg, 0.055 mmol) as a yellowsolid. Retention time: 5.736 min (CHIRALPAK IE-3. 0.46*10 cm; 3 μm;

-   MtBE(0.3% IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=488.2;    ¹HNMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.39 (s, 1H), 8.32 (s,    1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 6.86 (d, J=6.2 Hz,    1H), 6.21 (s, 2H), 5.68 (s, 1H), 4.30-4.29 (m, 2H), 3.77 (s, 3H),    3.38-3.37(m, 2H), 2.28-2.12 (m, 2H), 1.94 (s, 3H), 1.64-1.50 (m,    1H), 1.28 (d, J=6.1 Hz, 3H). Compound 35: (72.6 mg, 0.15 mmol) as a    yellow solid. Retention time: 7.063 min (CHIRALPAK IE-3. 0.46*10 cm;    3 μm; MtBE(0.3% IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI)    [M+H]⁺=488.2; ¹ HNMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.41 (s,    1H), 8.29 (s, 1H), 7.55 (s, 1H), 7.32 (s 1H), 7.29 (s, 1H), 6.84 (d,    J=6.2 Hz, 1H), 6.22 (s, 2H), 5.68 (s, 1H), 4.30-4.29 (m, 2H), 3.81    (s, 3H), 3.38-3.37 (m, 2H), 2.31 (dd, J=9.1, 4.5 Hz, 1H), 2.12 (t,    J=4.6 Hz, 1H), 1.93 (d, J=1.6 Hz, 3H), 1.67-1.54 (m, 1H), 0.97 (d,    J=6.3 Hz, 3H). Compound 36: (80.2 mg, 0.16 mmol) as a yellow solid.    Retention time: 9.167 min (CHIRALPAK IE-3. 0.46*10 cm; 3 μm;    MtBE(0.3% IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=488.2;    ¹HNMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.41 (s, 1H), 8.29 (s,    1H), 7.55 (s, 1H), 7.32 (s 1H), 7.29 (s, 1H), 6.84 (d, J=6.2 Hz,    1H), 6.22 (s, 2H), 5.68 (s, 1H), 4.30-4.29 (m, 2H), 3.81 (s, 3H),    3.38-3.37 (m, 2H), 2.31 (dd, J=9.1, 4.5 Hz, 1H), 2.12 (t, J=4.6 Hz,    1H), 1.93 (d, J=1.6 Hz, 3H), 1.67-1.54 (m, 1H), 0.97 (d, J=6.3 Hz,    3H).

Example 1362-((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 233)

Step 1: tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (1.14 g, 3.54mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(518.19 mg, 0.71 mmol), potassium carbonate (1.47 g, 10.62 mmol) andtert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (2.0 g, 5.32 mmol) in 1,4-dioxane (20 ml) andwater (4 mL) was stirred at 90° C. for 1 hour. The reaction was cooledto room temperature and then filtered. The filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (3/1) to affordtert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(1.5 g, 3.37 mmol) as a yellow solid.

Step 2:tert-butyl7-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(200 mg, 0.44 mmol) and2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(147 mg, 0.52 mmol), t-BuBrettphos Pd G3 (77 mg, 0.08 mmol),t-BuBrettphos (104 mg, 0.16 mmol), cesium carbonate (439 mg, 1.36 mmol)in 1,4-dioxane (40 mL) was stirred at 120° C. for 1 hour. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to affordtert-butyl7-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(150 mg, 0.024 mmol) as a yellow solid. LCMS (ESI) [M+I-I]⁺=517.24.

Step 3: tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl7-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(150 mg, 0.24 mmol), tert-butyl carbamate (552.4 mg, 4.8 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (48.82 mg, 0.048mmol),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(50.63 mg, 0.096 mmol) and cesium carbonate (230.49 mg, 0.71 mmol) in1,4-dioxane (10 mL) was stirred at 90° C. for 2 hours. After filtration,the solvent was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(100 mg, 0.14 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=717.8.

Step 4:2-[[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(100 mg, 0.07 mmol) and trifluoroacetic acid (2 mL, 0.07 mmol) indichloromethane (4 mL) was stirred at 25° C. for 1 hour. The solvent wasconcentrated under vacuum and then adjusted to pH 9 with ammonia inmethanol (7 mol/L). The residue was purified by prep-HPLC (SunFire PrepC18 OBD Column 19×150 mm 5 um 10 nm; Water (0.1%FA): CAN=9% B to 30% Bin 7 min; 25 mL/min) to afford2-[[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(10 mg, 0.019 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=517.24. ¹HNMR(300 MHz, Methanol-d₄) δ 9.11 (s, 1H), 7.59 (s, 1H), 7.36 (s, 1H), 6.81(d, J=6.2 Hz, 1H), 6.03 (s, 1H), 5.03 (s, 2H), 4.77-4.68 (m, 1H), 4.39(t, J=4.4 Hz, 2H), 3.89-3.79 (m, 2H), 3.48 (t, J=4.4 Hz, 2H), 3.10 (t,J=6.1 Hz, 2H), 2.02 (s, 3H), 1.21 (d, J=6.8 Hz, 6H).

Example 1371-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-[(1R)-1-(1-methylpyrazol-4-yl)ethyl]urea(Compound 111) and1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-[(15)-1-(1-methylpyrazol-4-yl)ethyl]urea(Compound 112)

Step 1: tert-butyl7-[8-chloro-7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

The title compound was prepared in a fashion analogous to that describedfor Example 133 (Compound 29) using tert-butyl7-(8-chloro-7-fluoro-3-(((4-nitrophenoxy)carbonyl)amino)isoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate.LCMS (ESI) [M+H]⁺=596.1.

Step 3: tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

The title compound was prepared in a fashion analogous to that describedfor Example 133 (Compound 29) using tert-butyl7-[8-chloro-7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylateLCMS (ESI) [M+H]⁺=677.3.

Step 4:148-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-[(1R)-1-(1-methylpyrazol-4-yl)ethyl]urea(Compound 111) and1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-[(1S)-1-(1-methylpyrazol-4-yl)ethyl]urea(Compound 112)

A solution of tert-butyl7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(80 mg, 0.12 mmol) and trifluoroacetic acid (2 mL, 25.96 mmol) indichloromethane (5 mL) was stirred at 25° C. for 1 hour. The reactionsolution was concentrated under vacuum and then adjusted to pH 8 withammonia in methanol (7 mol/L). The residue was purified by Prep-HPLC(X-Bridge Prep C18 OBD 5 μm, 19*150 mm; water (10 mmol/L sodiumbicarbonate): ACN=5% B to 45% B in 9 min) and chiral-HPLC to afford twoenantiomers: Compound 111:1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-[(1R)-(1-methylpyrazol-4-yl)ethyl]urea(assumed) (20.6 mg, 0.043 mmol) as a yellow solid. Rt=2.634 min (LuxCellulose-4, 0.46*15 cm; 3 μm, MtBE(0.1% DEA): EtOH=50:50, 1.0 ml/min).LCMS (ESI) [M+H]⁺=477.2; ¹HNMR (300 MHz, Methanol-d₄) δ 9.21 (s, 1H),7.61 (s, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.89 (d, J=6.2Hz, 1H), 5.08-5.02(m, 1H), 4.42 (t, J=4.2 Hz, 2H), 3.89 (s, 3H), 3.51(t, J=4.2 Hz, 2H), 2.03 (s, 3H), 1.57 (d, J=6.8 Hz, 3H). Compound 112:1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-[1(S)-(1-methylpyrazol-4-yl)ethyl]urea(20.7 mg, 0.043 mmol) as a yellow solid. Rt=3.544 (Lux Cellulose-4,0.46*15 cm, 3 μm; MtBE(0.1% DEA): EtOH=50:50, 1.0 ml/min). LCMS (ESI)[M+H]⁺=477.2; ¹HNMR (300 MHz, Methanol-d₄) δ 9.21 (s, 1H), 7.61 (s, 1H),7.58 (s, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.89 (d, J=6.2 Hz, 1H),5.08-5.02(m, 1H), 4.42 (t, J=4.2 Hz, 2H), 3.89 (s, 3H), 3.51 (t, J=4.2Hz, 2H), 2.03 (s, 3H), 1.57 (d, J=6.8 Hz, 3H).

Example 1382-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(Compound 234)

Step 1: tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-3-((5,5-dimethyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

A mixture of2-bromo-5,5-dimethyl-6,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(66.34 mg, 0.26 mmol), tert-butylN-[5-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(100.0 mg, 0.17 mmol), t-BuBrettphosPdG3 (58.53 mg, 0.07 mmol),t-BuBrettphos (41.55 mg, 0.09 mmol) and cesium carbonate (167.57 mg,0.51 mmol) in 1,4-dioxane (15 mL) was stirred for 1 hour at 120° C.under nitrogen. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (98/2) to affordtert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(5,5-dimethyl-7-oxo-6,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(60 mg, 0.08 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=761.

Step 2:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5,5,6-trimethyl-7-oxo-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(80.0 mg, 0.10 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (6 mL) was stirred at 25° C. for 2 hours. The solventwas concentrated under vacuum. The reaction mixture was adjusted to pH 9with ammonia in methanol (7 mol/L). The resulting residue was purifiedby reverse phase chromatography (acetonitrile 0-40/0.1% FA in water) toafford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(30.5 mg, 0.06 mmol,) as an orange solid. LCMS (ESI) [M+H]⁺=461.2; ¹HNMR (400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.10 (s, 1H), 7.99 (s, 1H),7.76-7.65 (m, 3H), 6.73 (d, J=6.0 Hz, 1H), 6.07 (s, 2H), 6.04 (s, 1H,5.41 (s, 2H), 4.83 (s, 2H), 3.05 (s, 2H), 1.96 (d, J=1.5 Hz, 3H), 1.18(s, 6H).

Example 1392-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,5,6-trimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 235)

Step 1: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5,5,6-trimethyl-7-oxo-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(65.28 mg, 0.24 mmol), tert-butylN-[5-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(100 mg, 0.17 mmol), t-BuBrettphosPdG3 (58.53 mg, 0.07 mmol),t-BuBrettphos (41.55 mg, 0.09 mmol) and cesium carbonate (167.57 mg,0.51 mmol) in 1,4-dioxane (10 mL) was stirred for 1 hour at 120° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol (100/3) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5,5,6-trimethyl-7-oxo-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(80 mg, 0.10 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=775.

Step 2:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one;formic acid

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5,5,6-trimethyl-7-oxo-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(80 mg, 0.10 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (6 mL) was stirred at 25° C. for 2 hours. The solventwas concentrated under vacuum. The reaction mixture was adjusted to pH 9with ammonia in methanol (7 mol/L). The mixture was concentrated undervacuum. The resulting residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% FA in water) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-5,5,6-trimethyl-4,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one;formic acid (30.5 mg, 0.059 mmol) as an orange solid. LCMS (ESI)[M+H]⁺=475; ¹HNMR (400 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.11 (s, 1H), 7.98(s, 1H), 7.69-7.67 (d, J=7.2 Hz, 2H), 6.70-6.69 (d, J=7.2 Hz, 1H), 6.05(s, 3H), 5.26 (s, 2H), 4.94 (s, 2H), 3.20 (s, 2H), 2.76 (s, 3H), 1.93(s, 3H), 1.28 (s, 6H).

Example 140(1S,2S,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 239),(1R,2R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 237),(1R,2R,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 238), and(1S,2S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 236)

Step 1: trans-tert-butyl2-(benzyloxymethyl)-3-methylcyclopropanecarboxylate

The title compound was prepared in a fashion analogous to that describedfor Example 135 (Compound 36) using (E)-tert-butyl4-(benzyloxy)but-2-enoate. LCMS (ESI) [M+I-I]⁺=277.

Step 2: trans-2-(benzyloxymethyl)-3-methylcyclopropanecarboxylic acid

The title compound was prepared in a fashion analogous to that describedfor Example 135 (Compound 36) using trans-tert-butyl2-(benzyloxymethyl)-3-methylcyclopropanecarboxylate. LCMS (ESI)[M+H]⁺=221.

Step 3: trans-tert-butylN-[5-[3-[[2-(benzyloxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-8-chloro-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

The title compound was prepared in a fashion analogous to that describedfor Example 135 (Compound 36) usingtrans-2-(benzyloxymethyl)-3-methyl-cyclopropanecarboxylic acid. LCMS(ESI) [M+H]⁺=705.

Step 4: tert-butylN-[5-[3-[[tans-2-(benzyloxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

The title compound was prepared in a fashion analogous to that describedfor Example 135 (Compound 36) using trans-tert-butylN-[5-[3-[[2-(benzyloxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-8-chloro-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate.LCMS (ESI) [M+H]⁺=786.

Step 5: trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[2-(hydroxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A solution of trans-tert-butylN-[5-[3-[[2-(benzyloxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(1.1 g, 1.4 mmol) and Pd(OH)₂/C (979.77 mg, 1.4 mmol)in methanol (30 mL)was stirred for 36 hours at 25° C. under a hydrogen atmosphere. Afterfiltration, the filtrate was concentrated under vacuum to affordtrans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[2-(hydroxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(450 mg, 0.65 mmol) as a color solid. LCMS (ESI) [M+H]⁺=696.

Step 6:trans-[2-[[6-[5-[bis(tert-butoxycarbonyl)amino]-4-methyl-3-pyridyl]-8-(tert-butoxycarbonylamino)-7-fluoro-3-isoquinolyl]carbamoyl]-3-methyl-cyclopropyl]methylmethanesulfonate

To a solution of trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[2-(hydroxymethyl)-3-methyl-cyclopropanecarbonyl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(450 mg, 0.65 mmol) and triethylamine (195.97 mg, 1.94 mmol) indichloromethane (15 mL) was added methanesulfonyl chloride (187.56 mg,1.29 mmol) at 0° C. The resulting solution was stirred for 1 hour at 25°C. The reaction was quenched with water, extracted with dichloromethaneand dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated under vacuum to affordtrans-[2-[[6-[5-[bis(tert-butoxycarbonyl)amino]-4-methyl-3-pyridyl]-8-(tert-butoxycarbonylamino)-7-fluoro-3-isoquinolyl]carbamoyl]-3-methyl-cyclopropyl]methylmethanesulfonate (450 mg, 0.58 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=774.

Step 7: trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[2-(cyanomethyl)-3-methyl-cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A solution oftrans-[2-[[6-[5-[bis(tert-butoxycarbonyl)amino]-4-methyl-3-pyridyl]-8-(tert-butoxycarbonylamino)-7-fluoro-3-isoquinolyl]carbamoyl]-3-methyl-cyclopropyl]methylmethanesulfonate (450 mg, 0.58 mmol) and potassium cyanide (113.39 mg,1.74 mmol) in dimethyl sulfoxide (10 mL) was stirred at 60° C. for 12hours. The reaction was quenched with a solution of ferrous sulfate andthen extracted with acetic ether. The organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated under vacuum toafford trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[2-(cyanomethyl)-3-methyl-cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(400 mg, 0.57 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=705.

Step 8:(1S,2S,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide,(1R,2R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide,(1R,2R,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide,(1S,2S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide

The title compound was prepared in a fashion analogous to that describedfor Example 135 (Compound 36) using trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[2-(cyanomethyl)-3-methyl-cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(400 mg, 0.57 mmol). The mixture was purified by chiral SFC separationto afford four isomers (Cyclopropane stereochemistry for each isomer:cyanomethyl trans to amide; methyl relative stereochemistry arbitrarilyassigned; All absolute stereochemistry arbitrarily assigned): Compound236: (14.5 mg, 0.036 mmol) as a yellow solid. Retention time: 8.931 min(CHIRALPAK IE-3. 0.46*10 cm; 3 μm;

-   MtBE(0.1% DEA):MeOH=95:5; 1.0 ml/min); LCMS (ESI) [M+H]⁺=405.2;    ¹HNMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.38 (s, 1H), 8.27 (s,    1H), 7.97 (s, 1H), 7.63 (s, 1H), 6.85 (d, J=6.2 Hz, 1H), 6.22 (s,    2H), 5.22 (s, 2H), 2.82-2.59 (m, 2H), 2.06 (dd, J=9.1, 4.7 Hz, 1H),    1.89 (d, J=1.4 Hz, 3H), 1.54-1.48 (m, 1H), 1.34 (dt, J=8.9, 6.1 Hz,    1H), 1.14 (d, J=6.1 Hz, 3H). Compound 237: (14.7 mg, 0.036 mmol) as    a yellow solid. Retention time: 10.678 min (CHIRALPAK IE-3. 0.46*10    cm; 3 μm; MtBE(0.1% DEA):MeOH=95:5; 1.0 ml/min); LCMS (ESI)    [M+H]⁺=405.2; ¹HNMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.38 (s,    1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 6.85 (d, J=6.2 Hz,    1H), 6.22 (s, 2H), 5.22 (s, 2H), 2.82-2.59 (m, 2H), 2.06 (dd, J=9.1,    4.7 Hz, 1H), 1.89 (d, J=1.4 Hz, 3H), 1.54-1.48 (m, 1H), 1.34 (dt,    J=8.9, 6.1 Hz, 1H), 1.14 (d, J=6.1 Hz, 3H). Compound 238: (15.3 mg,    0.038 mmol) as a yellow solid. Retention time: 4.185 min (CHIRALPAK    0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):EtOH=80:20; 1.0 ml/min); LCMS (ESI)    [M+H]⁺=405.2;¹HNMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.38 (s, 1H),    8.23 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 6.83 (d, J=6.2 Hz, 1H),    6.23 (s, 2H), 5.24 (s, 2H), 2.86-2.58 (m, 2H), 1.89 (d, J=1.5 Hz,    3H), 1.76 (t, J=4.5 Hz, 1H), 1.70-1.53 (m, 1H), 1.52-1.38 (m, 1H),    1.15 (d, J=6.4 Hz, 3H). Compound 239: (15.5 mg,0.038 mmol) as a    yellow solid. Retention time: 6.037 min (CHIRALPAK IE-3. 0.46*10 cm;    3 μm; MtBE(0.1% DEA):EtOH=80:20; 1.0 ml/min); LCMS (ESI)    [M+H]⁺=405.2; ¹HNMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.38 (s,    1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 6.83 (d, J=6.2 Hz,    1H), 6.23 (s, 2H), 5.24 (s, 2H), 2.86-2.58 (m, 2H), 1.89 (d, J=1.5    H.

Example 1412-((8-amino-7-fluoro-6-((2-oxo-1,2-dihydropyridin-3-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 240)

Step 1: 2-methoxy-3-pyridyl)methanol

A solution of 2-methoxynicotinic acid (200.0 mg, 1.31mmol) and boranetetrahydrofuran complex solution (1 mol/L) (4 mL, 3.92 mmol) was stirredunder nitrogen in tetrahydrofuran (5 mL) at 0° C. The resulting solutionwas stirred for 1 hour at 25° C. The reaction was quenched by methanol(2 mL). The solvent was concentrated under vacuum to afford2-methoxy-3-pyridyl)methanol (150 mg, 1.08 mmol) as a yellow oil. LCMS(ESI) [M+H]⁺=139.2.

Step 2: 3-(chloromethyl)-2-methoxypyridine

A solution of (2-methoxy-3-pyridyl)methanol (1.0 g, 7.19 mmol) and SOCl₂(2.56 g, 21.55 mmol) in dichloromethane (5 mL) was stirred at 25° C. for3 hours. The solvent was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (5 95) to afford3-(chloromethyl)-2-methoxypyridine (500 mg, 3.17 mmol) as a yellow oil.LC/MS (ESI) [M+H]⁺=157.6.

Step 3: tert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-6-((2-methoxypyridin-3-yl)methyl)isoquinolin-8-yl)carbamate

A mixtureof(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)boronicacid (86.96 mg, 0.17 mmol), 3-(chloromethyl)-2-methoxy-pyridine (40.0mg, 0.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.35 mg,0.03 mmol) and cesium carbonate (165.22 mg, 0.51 mmol) intetrahydrofuran (1 mL) and water (0.10 mL) was stirred forl hour at 100°C. The solvent was concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting withmethanol/dichloromethane (1/5) to afford tert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-6-((2-methoxypyridin-3-yl)methyl)isoquinolin-8-yl)carbamate(76 mg, 0.13 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=589.7.

Step 4:2-((8-amino-7-fluoro-6-((2-oxo-1,2-dihydropyridin-3-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A mixture of tert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-6-((2-methoxypyridin-3-yl)methyl)isoquinolin-8-yl)carbamate(60 mg, 0.10 mmol), lithium chloride (54 mg, 1.29 mmol) andp-toluenesulfonic acid (240 mg, 1.26 mmol) in N,N-dimethylformamide (5mL) was stirred at 120° C. for 0.5 h. The residue was purified by flashchromatography on C18 (acetonitrile-0.1% sodium bicarbonate in water) toafford2-((8-amino-7-fluoro-6-((2-oxo-1,2-dihydropyridin-3-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(5.1 mg, 0.01 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=476.2; ¹H NMR(300 MHz, DMSO-d₆) δ 11.59 (s, 1H), 9.17 (s, 1H), 9.00 (s, 1H), 7.57 (s,1H), 7.27-7.25 (m, 1H), 7.12 (d, J=6.7 Hz, 1H), 6.69 (d, J=6.6 Hz, 1H),6.14-6.09 (m, 1H), 5.95-5.88 (m, 3H), 4.96 (s, 2H), 4.61-4.57(m, 1H)3.78 (s, 4H), 2.99 (s, 2H), 1.13 (d, J=6.8 Hz, 6H).

Example 142N-(8-amino-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)ethanesulfonamide(Compound 241)

Step 1:tert-butyl (3-amino-8-chloroisoquinolin-6-yl)carbamate

A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (1.0 g, 3.88 mmol),tert-butyl carbamate (13.65 g, 116.5 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (803.85 mg, 0.78mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (897.83 mg, 1.55mmol) and cesium carbonate (6.33 g, 19.42 mmol) in 1,4-dioxane (30mL)was stirred at 90° C. for 2 hours. The solvent was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with petroleum ether/ethyl acetate (1/2) to afford tert-butylN-(3-amino-8-chloro-6-isoquinolyl)carbamate (500 mg, 1.70 mmol) as ayellow solid. LCMS (ESI) [M+H]⁺=294.

Step 2:tert-butyl(8-chloro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)carbamate

A solution of tert-butyl N-(3-amino-8-chloro-6-isoquinolyl)carbamate(300 mg, 1.02 mmol), tert-butylN-(3-amino-8-chloro-6-isoquinolyl)carbamate (300 mg, 1.02 mmol),t-BuBrettphosPdG3 (348.87 mg, 0.41 mmol), t-BuBrettphos (247.15 mg, 0.51mmol) and cesium carbonate (1.66 g, 5.11 mmol) in 1,4-dioxane (50 mL)was stirred at 120° C. for 1 hour. The solvent was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (97/3) to afford tert-butylN-[8-chloro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]carbamate(279 mg, 0.58 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=485.

Step3:2-((6-amino-8-chloroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[8-chloro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]carbamate(270 mg, 0.56 mmol) in 2,2,2-trifluoroacetic acid (10 mL) was stirred at25° C. for 1 hour. The solvent was concentrated under vacuum. Thereaction mixture was adjusted to pH 10 with ammonia in methanol (7mol/L). The resulting residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% NH₄CO₃ in water) to afford2-[(6-amino-8-chloro-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(200 mg, 0.52 mmol) as a gray solid. LCMS (ESI) [M+H]⁺=385.

Step 4:N-(8-chloro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)ethanesulfonamide

To a solution of2-[(6-amino-8-chloro-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(200 mg, 0.52 mmol) and triethylamine (262.43 mg, 2.60 mmol) indichloromethane (2 mL) was added ethanesulfonyl chloride (200.46 mg,1.56 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0°C. The organic layer was concentrated under vacuum. Then sodiumhydroxide (500 mg, 20.83 mmol) in water (10 mL) was added and stirred at25° C. for 1 hour. The resulting solution was extracted with ethylacetate, dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The resulting residue waspurified by reverse phase chromatography (acetonitrile 0-40/0.1% NH₄CO₃in water) to affordN-[8-chloro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]ethanesulfonamide(85 mg, 0.18 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=477.

Step 5:tert-butyl(6-(ethylsulfonamido)-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-8-yl)carbamate

A mixture ofN-[8-chloro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]ethanesulfonamide(80 mg, 0.17 mmol), tert-butyl carbamate (491.22 mg, 4.19 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (69.44 mg, 0.07mmol), Brettphos (71.92 mg, 0.13 mmol) and cesium carbonate (164.03 mg,0.50 mmol) in 1,4-dioxane (8 mL) was stirred at 120° C. for 1 hour. Thesolvent was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(96/4) to afford tert-butylN-[6-(ethylsulfonylamino)-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(35 mg, 0.063 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=558.

Step6:N-(8-amino-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)ethanesulfonamide

A solution of tert-butylN-[6-(ethylsulfonylamino)-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(30 mg, 0.05 mmol) and 2,2,2-trifluoroacetic acid (3 mL) was stirred at25° C. for 1 hour. The reaction solution was concentrated under vacuum.The residue was adjusted to pH 10 with ammonia in methanol (7 mol/L).The crude product was purified by prep-HPLC with (XSelect CSH Prep C18OBD Column, 19*250 mm, 5 um; Water (0.1%FA): ACN (5%-70%) in 7 min; 25mL/min) to affordN-[8-amino-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]ethanesulfonamide;formic acid (14 mg, 0.028 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=458; ¹HNMR (300 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.00 (s, 2H), 7.40(s, 1H), 6.57 (d, J=1.8 Hz, 1H), 6.33 (d, J=1.9 Hz, 1H), 6.19 (s, 2H),6.00 (s, 1H), 4.97 (s, 2H), 4.61 (m, 1H), 3.90-3.71 (m, 2H), 3.19 (m,2H), 3.00 (d, J=6.1 Hz, 2H), 1.22 (m, 3H), 1.14 (d, J=6.8 Hz, 6H).

Example 1435-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-ethyloxazol-2(3H)-one(Compound 242)

Step 1: 4-ethyl-3H-oxazol-2-one

A solution of potassium cyanate (6.0 g, 74.07 mmol),1-hydroxybutan-2-one (3.0 g, 34.05 mmol) in diethyl ether (100 mL) wasadded acetic acid (3.0 mL, 34.05 mmol) was stirred at 20° C. for 12 h.After filtration, the filtrate was concentrated under reduced pressureto afford 4-ethyl-3H-oxazol-2-one (1.0 g, 8.84 mmol) as yellow oil. LCMS(ESI) [M+H]⁺=114.

Step 2: 4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one

Sodium hydride (579.52 mg, 60% purity, 25.2 mmol) was added to asolution of 4-ethyl-3H-oxazol-2-one (1.9 g, 16.8 mmol) inN,N-dimethylformamide (30 mL) at 0° C. The solution was stirred at 0° C.for 10 minutes. 4-Methoxybenzylchloride (3.14 g, 20.16 mmol) was addedand stirred at 25° C. for 2 hours. The reaction solution was dilutedwith ethyl acetate and washed with water. The organic extract was driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by reverse phaseflash water (10 mmol/1 sodium bicarbonate) /ACN(60/40) to afford4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one (2.1 g, 9.00 mmol) as alight yellow solid. LCMS (ESI) [M+H]⁺=234.

Step 3:5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one

A solution of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (287 mg, 0.89mmol), 4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one (207.58 mg, 0.89mmol), tricyclohexyl phosphine (49.83 mg, 0.18 mmol), palladium acetate(29.01 mg, 0.09 mmol), pivalic acid (22.69 mg, 0.22 mmol) and potassiumcarbonate (245.61 mg, 1.78 mmol) in N,N-dimethylacetamide (4 mL) wasstirred at 100° C. for 3 hours and then concentrated The residue waspurified by reverse column eluting with water (sodium bicarbonate 10mmol/L)/ACN (30/70) to afford5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one(225 mg, 0.53 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=428.

Step 4:5-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one

A solution of5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one(225 mg, 0.53 mmol),2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(171.73 mg, 0.63 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (108.86 mg, 0.11mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (121.58 mg, 0.21mmol) and cesium carbonate (514.3 mg, 1.58 mmol) in 1,4-dioxane (20 mL)was stirred at 100° C. for 12 hours. The mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (96/4) to afford5-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one(158 mg, 0.26 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=619.

Step 5: tert-butylN-[6-[4-ethyl-3-[(4-methoxyphenyl)methyl]-2-oxo-oxazol-5-yl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of5-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-ethyl-3-[(4-methoxyphenyl)methyl]oxazol-2-one(155 mg, 0.25 mmol), tert-butyl carbamate (732.32 mg, 6.26 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (51.83 mg, 0.05mmol), Brettphos (40.26 mg, 0.08 mmol), and cesium carbonate (244.86 mg,0.75 mmol) in 1,4-dioxane (12 mL) was stirred at 90° C. for 2 hours. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(96/4) to afford tert-butylN-[6-[4-ethyl-3-[(4-methoxyphenyl)methyl]-2-oxo-oxazol-5-yl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(80 mg, 0.11 mmol) as a light yellow solid. LCMS (ESI) [M+U]⁺=700.

Step 6:5-[8-amino-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-ethyl-3H-oxazol-2-one

A solution of tert-butylN-[6-[4-ethyl-3-[(4-methoxyphenyl)methyl]-2-oxo-oxazol-5-yl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(140 mg, 0.20 mmol) in 2,2,2-trifluoroacetic acid (5.0 mL) andtrifluoromethanesulfonic acid (1.0 mL) was stirred at 25° C. for 48hours. The crude product was purified by prep-HPLC [XBridge Prep C18 5um×30 mm×150 mm; water (sodium bicarbonate 10 mmol/L):ACN(15%-50%) in6.03 min] to afford5-[8-amino-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-ethyl-3H-oxazol-2-one(33mg, 0.069 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=480; ¹HNMR (400MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.21 (s, 1H), 9.09 (s, 1H), 7.66 (s, 1H),6.86 (d, J=6.0 Hz, 1H), 6.13 (s, 2H), 5.98 (s, 1H), 4.98 (s, 2H),4.65-4.56 (m, 1H), 3.78 (t, J=6.0 Hz, 2H), 2.98 (t, J=6.0 Hz, 2H),2.51-2.47 (m, 2H), 1.21-1.12 (m, 9H).

Example 1442-((8-amino-6-(5-amino-4-chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 243)

Step 1: 4-chloro-5-iodo-pyridin-3-amine

To a solution of 4-chloro-3-iodo-5-nitro-pyridine (1.0 g, 3.52 mmol) indiethyl ether (10 mL) was added hydrochloric acid (7.4 mL, 3.52 mmol)and stannous chloride (8.0 g, 35.4 mmol) at 25° C. The mixture wasstirred at rt for 2 hours. The reaction was quenched with ammonia inmethanol (7 mol/L). The resulting solution was extracted with ethylacetate, dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum to afford4-chloro-5-iodo-pyridin-3-amine (800 mg, 3.14 mmol) as a yellow solid.LCMS (ESI) [M+H]⁺=254.5.

Step 2: tert-butylN-[6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

Under nitrogen, a solution of 4-chloro-5-iodo-pyridin-3-amine (74.0 mg,0.29 mmol),[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid (50.0 mg, 0.10 mmol), potassium phosphate (20.0 mg, 0.09 mmol),sodium acetate (23.85 mg, 0.29 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg,0.02 mmol) in acetonitrile (1 mL) and water (0.10 mL). The resultingsolution was stirred for 1 hour at 90° C. The solvent was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with methanol/dichloromethane (5/95) to afford tert-butylN-[6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(50 mg, 0.084 mmol) as a yellow solid. LC/MS (ESI) [M+H]⁺=595.1.

Step 3:2-((8-amino-6-(5-amino-4-chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(50.0 mg, 0.08 mmol) and TFA (1 mL, 0.08 mmol) in dichloromethane (5 mL)was stirred at 25° C. for 2 hours. The reaction mixture was adjusted topH 7 with ammonia in methanol (7 mol/L). The residue was purified byflash chromatography on C18 (acetonitrile-0.1% sodium bicarbonate inwater) to afford2-((8-amino-6-(5-amino-4-chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(12.9 mg, 0.026 mmol) as a red solid. LCMS (ESI) [M+H]⁺=495.2. ¹HNMR(300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.08 (s, 1H), 8.13 (s, 1H), 7.73 (s,1H), 7.70 (s, 1H), 6.77 (d, J=5.9 Hz, 1H), 6.09 (s, 2H), 5.94 (s, 1H),5.77 (s, 2H), 4.94 (s, 2H), 4.63-4.51 (m, 1H), 3.81-3.70 (m, 2H),2.99-2.91 (m, 2H), 1.10 (d, J=6.8 Hz, 6H).

Example 1452-((8-amino-7-fluoro-6-((4-methyl-2-oxopiperazin-1-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 244)

Step 1: (3-amino-8-chloro-7-fluoro-6-isoquinolyl)methanol

A solution of tributylstannylmethanol (3.98 g, 12.4 mmol),8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (2.0 g, 6.2 mmol) andtetrakis(triphenylphosphine)palladium (1.43 g, 1.24 mmol) in 1,4-dioxane(20 mL) was stirred for 60 hours at 90° C. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford (3-amino-8-chloro-7-fluoro-6-isoquinolyl)methanol (550mg, 2.43 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=227.

Step 2:2-[[8-chloro-7-fluoro-6-(hydroxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of 3-amino-8-chloro-7-fluoro-6-isoquinolyl)methanol (200mg, 0.88 mmol),2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(264.18 mg, 0.97 mmol), t-BuBrettphos (213.56 mg, 0.44 mmol) andt-BuBrettphos PdG3 (301.46 mg, 0.35 mmol) in 1,4-dioxane (40 mL) wasadded cesium carbonate (1.44 g, 4.41 mmol) at 25° C. The resultingsolution was stirred for 1 hour at 120° C. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(9/1) to afford2-[[8-chloro-7-fluoro-6-(hydroxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(120 mg, 0.29 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=418.

Step 3:2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of2-[[8-chloro-7-fluoro-6-(hydroxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.12 mmol) and thionyl chloride (70.6 mg, 0.60 mmol) indichloromethane (5 mL) was stirred at 25° C. for 1 hour. The solvent wasconcentrated under vacuum to afford2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.11 mmol) as a color solid. LCMS (ESI) [M+H]+=436.

Step 4:2-[[8-chloro-7-fluoro-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of 4-methyl-2-piperazinone (26.16 mg, 0.23 mmol) inN,N-dimethylformamide (3mL) was added sodium hydride (18.34 mg, 60%purity, 0.46 mmol) at 0° C. The reaction was stirred for 20 minutes at0° C.2-[[8-Chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.11 mmol) was added and stirred at 25° C. for 1 hour. Thereaction was quenched with water, extracted with ethyl acetate, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% sodium bicarbonate in water) toafford2-[[8-chloro-7-fluoro-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(9 mg, 0.018 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=514.

Step 5: tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-8-isoquinolyl]carbamate

To a mixture of2-[[8-chloro-7-fluoro-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(46 mg, 0.09 mmol), tert-Butyl carbamate (314.53 mg, 2.68 mmol),tris(dibenzylideneacetone)dipalladium (18.53 mg, 0.02 mmol) andBrettphos (19.22 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was added cesiumcarbonate (116.7 mg, 0.36 mmol) at 25° C. The reaction was stirred for 3hours at 90° C. After filtration, the filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (9/1) to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-8-isoquinolyl]carbamate(45 mg, 0.076 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=595.

Step 6:2-[[8-amino-7-fluoro-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-8-isoquinolyl]carbamate(43 mg, 0.07 mmol) in 2,2,2-trifluoroacetic acid (2 mL) anddichloromethane (4 mL) was stirred at 25° C. for 2 hours. The mixturewas concentrated under vacuum. The residue was purified by prep-HPLC(Atlantis HILIC OBD, 19×150 mm 5 um; water (0.1% FA): CH3CN=7%-15% B in7 min) to afford2-[[8-amino-7-fluoro-6-[(4-methyl-2-oxo-piperazin-1-yl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(15.5 mg, 0.029 mmol) as a red solid. LCMS (ESI) [M+H]⁺=495.3; ¹HNMR(300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 9.04 (s, 1H), 8.12 (s, 1H), 7.57 (s,1H), 6.63 (d, J=6.0 Hz, 1H), 5.99 (s, 1H), 5.94 (s, 1H), 4.95 (s, 2H),4.66-4.50 (m, 3H), 3.76 (t, J=5.9 Hz, 2H), 3.3-3.2 (m, 2H), 3.19 (s,2H), 2.96 (t, J=5.5 Hz, 2H), 2.88-2.64 (m, 2H), 2.32 (s, 3H), 1.10 (d,J=6.8 Hz, 6H).

Example 1465-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-N,N,4-trimethylpyrimidine-2-carboxamide(Compound 245)

Step 1: 5-bromo-4-methyl-pyrimidine-2-carbonitrile

A solution of sodium cyanide (1062.86 mg, 21.69 mmol) and1,4-diazabicyclooctane triethylenediamine (323.92 mg, 2.89 mmol) indimethyl sulfoxide (2 mL) and water (2 mL) was stirred at 25° C. for 1hour. A solution of 5-bromo-2-chloro-4-methylpyrimidine (3.0 g, 14.46mmol) in dimethyl sulfoxide was added and stirred for 12 hours. Thereaction was quenched with ferrous sulfate in water. The resultingsolution was extracted with ethyl acetate, dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (5/95) to afford5-bromo-4-methyl-pyrimidine-2-carbonitrile (700 mg, 3.54 mmol) as ayellow solid. LCMS (ESI) [M+H]⁺=198.0.

Step 2: 5-bromo-4-methyl-pyrimidine-2-carboxylic acid

A solution of 5-bromo-4-methyl-pyrimidine-2-carbonitrile (1.0 g, 5.05mmol) and NaOH (606 mg, 15.15 mmol) in water (40 mL) was stirred at 60°C. for 2 hours. The reaction mixture was adjusted to pH 2 withhydrochloric acid (2 mol/L). The resulting solution was extracted withethyl acetate, dried with anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum to afford5-bromo-4-methyl-pyrimidine-2-carboxylic acid (800 mg, 3.69 mmol) aslight yellow oil. LCOMS (ESI) [M+H]⁺=217.0.

Step 3: 5-bromo-N,N,4-trimethyl-pyrimidine-2-carboxamide

To a solution of 5-bromo-4-methyl-pyrimidine-2-carboxylic acid (1.0 g,4.61 mmol), N,N-dimethylamine (311.58 mg, 6.91 mmol) andN,N-diisopropylethylamine (2377.66 mg, 18.43 mmol) inN,N-dimethylformamide (30 mL) was added2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (2628.08 mg, 6.91 mmol). The mixture was stirred at25° C. for 12 hours and then quenched by water. The resulting solutionwas extracted with ethyl acetate, dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withmethanol/dichloromethane (5/95) to afford5-bromo-N,N,4-trimethyl-pyrimidine-2-carboxamide (600 mg, 2.46 mmol) asa yellow oil. LC/MS (ESI) [M+H]⁺=244.1.

Step 4: tert-butylN-[6-[2-(dimethylcarbamoyl)-4-methyl-pyrimidin-5-yl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid (50.0 mg, 0.10 mmol),5-bromo-N,N,4-trimethyl-pyrimidine-2-carboxamide (47.64 mg, 0.20 mmol),terakis(triphenylphosphine)palladium (22.56 mg, 0.02 mmol) and potassiumcarbonate (40 mg, 0.29 mmol) in 1,4-dioxane (5 mL) and water (1 mL) wasstirred at 90° C. for 1 hour. The solvent was concentrated under vacuum.The residue was purified by reverse column eluting with sodiumbicarbonate (10 mmol/L)/ACN (70/30) to afford tert-butylN-[6-[2-(dimethylcarbamoyl)-4-methyl-pyrimidin-5-yl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(40 mg, 0.063 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=631.7.

Step 5: tert-butylN-[6-[2-(dimethylcarbamoyl)-4-methyl-pyrimidin-5-yl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of tert-butylN-[6-[2-(dimethylcarbamoyl)-4-methyl-pyrimidin-5-yl]-'7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(5.0 mg, 0.010 mmol) and 2,2,2-trifluoroacetic acid (0.2 mL) indichloromethane (2 mL) was stirred at 25° C. for 3 hours. The reactionmixture was adjusted to pH 7 with ammonia in methanol (7 mol/L). Themixture was concentrated under vacuum. The residue was purified by flashchromatography on C18 (acetonitrile-0.1% sodium bicarbonate in water) toafford5-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-N,N,4-trimethylpyrimidine-2-carboxamide(9.1 mg, 0.017 mmol) as an orange solid. LCMS (ESI) [M+H]⁺=532.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.16 (s, 1H), 8.77 (s, 1H), 7.78 (s,1H), 6.92 (d, J=6.1 Hz, 1H), 6.23 (s, 2H), 5.96 (s, 1H), 4.96 (s, 2H),4.56-4.58 (m, 1H), 3.80-3.77 (m, 2H), 3.05 (s, 3H), 2.98-2.90 (m, 2H),2.86 (s, 3H), 2.45 (d, J=1.2 Hz, 3H), 1.12 (d, J=6.8 Hz, 6H).

Example 1472-((8-amino-6-(5-amino-4-methoxypyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 246)

Step 1: 3-bromo-4-methoxy-5-nitro-pyridine

A solution of 3-bromo-4-chloro-5-nitropyridine (3.0 g, 12.63 mmol),methanol (4.68 mL) and potassium carbonate (3.49 g, 25.27 mmol) inN,N-dimethylformamide (3 mL) was stirred at 25° C. for 1 hour. Thesolvent was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with methanol /dichloromethane(2/98) to afford 3-bromo-4-methoxy-5-nitro-pyridine (600 mg, 2.57 mmol)as a colorless oil. LCMS (ESI) [M+H]⁻=233.0.

Step 2: [tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(4-methoxy-5-nitro-3-pyridyl)-8-isoquinolyl]carbamate

A mixture of[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolylboronic acid (102.94 mg, 0.20 mmol), 3-bromo-4-methoxy-5-nitro-pyridine(70.0 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium (47.35 mg,0.04 mmol) and potassium carbonate (82.35 mg, 0.60 mmol) in 1,4-dioxane(1 mL) and water (0.10 mL) was stirred at 90° C. for 1 hour. The mixturewas concentrated under vacuum. The residue was purified by flashchromatography on C18 eluting with ACN/water (70%) to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(4-methoxy-5-nitro-3-pyridyl)-8-isoquinolyl]carbamate(60 mg, 0.097 mmol) as a brown oil. LCMS (ESI) [M+H]⁺=620.6.

Step 3: [tert-butylN-[6-(5-amino-4-methoxy-3-pyridyl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(4-methoxy-5-nitro-3-pyridyl)-8-isoquinolyl]carbamate(70 mg, 0.11 mmol) and raney nickel (10 mg, 0.11 mmol)] in methanol (5mL) was stirred at 25° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on C18 eluting with ACN/water (60%) to afford [tert-butylN-[6-(5-amino-4-methoxy-3-pyridyl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(40 mg, 0.07 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=590.6.

Step 4:2-((8-amino-6-(5-amino-4-methoxypyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A mixture of tert-butylN-[6-(5-amino-4-methoxy-3-pyridyl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(40.0 mg, 0.07 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (5 mL) was stirred at 25° C. for 3 hours. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH 7with ammonia in methanol (7 mol/L). The residue was purified by flashchromatography on C18 (acetonitrile-0.1% sodium bicarbonate in water) toafford2-((8-amino-6-(5-amino-4-methoxypyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(6.1 mg, 0.012 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=491.3. ¹H NMR(400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.06 (s, 1H), 8.05 (s, 1H), 7.72 (s,1H), 7.68 (s, 1H), 6.83 (d, J=6.0 Hz, 1H), 6.04 (s, 2H), 5.96 (s, 1H),5.22 (s, 2H), 4.96 (s, 2H), 4.62-4.55 (m, 1H), 3.81-3.73 (m, 2H), 3.45(s, 3H), 3.02-2.94 (m, 2H), 1.12 (d, J=6.8 Hz, 6H).

Example 1486-(5-amino-4-methylpyridin-3-yl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8-diamine(Compound 247)

Step 1: 2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-7-thione

A solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (1.0 g,4.35 mmol) and Lawesson's reagent (1.8 g, 4.45 mmol) in 1,4-dioxane (30mL) was stirred at 90° C. for 1 hour. The solvent was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (20/1) to afford2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-7-thione (530mg, 2.15 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=246.1.

Step 2:2-bromo-N-(2,2-diethoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-amine

A solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-7-thione (1.2 g,4.88 mmol), aminoacetaldehyde diethyl acetal (3.25 g, 24.38 mmol) andAg₂CO₃ (2.69 g, 9.75 mmol) in tetrahydrofuran (100 mL) was stirred at85° C. for 1 hour. After filtration, the filtrate was concentrated underreduced pressure. The resulting residue was purified by reverse phasechromatography (acetonitrile 0.05% TFA in water) to afford2-bromo-N-(2,2-diethoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-amine(900 mg, 2.6 mmol) as yellow solid . LC/MS (ESI) [M+H]⁺=245.2.

Step 3:8-bromo-5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepine

A solution of2-bromo-N-(2,2-diethoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-amine(425 mg, 1.23 mmol) and hydrochloric acid (0.31 mL, 1.23 mmol) in aceticacid (10 mL) was stirred at 80° C. for 1 hour. The solvent wasconcentrated under vacuum. The residue was purified by reverse-phasecolumn eluting with water (0.05% 2,2,2-trifluoroacetic acid)/acetonitrile (85/15) to afford8-bromo-5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepine (200mg, 0.79 mmol)as a brown oil. LCMS (ESI) [M+H]⁺=253.1.

Step 4: tert-butylN-[5-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(500 mg, 0.99 mmol), tert-butyl carbamate (3489.27 mg, 29.82 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (205.78 mg, 0.20mmol), Brettphos (159.85 mg, 0.30 mmol) and cesium carbonate (972.22 mg,2.98 mmol) in 1,4-dioxane (50 mL) was stirred at 90° C. for 1 hour. Thesolvent was concentrated under vacuum. The residue was purified byreverse column eluting with sodium bicarbonate (10 mmol/L) inwater/acetonitrile (40/60) to afford tert-butylN-[5-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(100 mg, 0.17 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=583.7.

Step 5: tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

A solution of tert-butylN-[5-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(130 mg, 0.20 mmol),8-bromo-5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepine(249.6 mg, 1.0 mmol), t-BuBretphosG3 (145.6 mg, 0. 20 mmol),t-BuBretophos (108 mg, 0. 20 mmol) and cesium carbonate (421.2 mg, 1.30mmol)] in 1,4-dioxane (10 mL) at 120° C. for 1 hour. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/1) to afford tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(70 mg, 0.10 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=755.8.

Step 6:6-(5-amino-4-methylpyridin-3-yl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8-diamine

A mixture of tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-3-((5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(70 mg, 0.09 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (5 mL) was stirred at 25° C. for 3 hours. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH 7with ammonia in methanol (7 mol/L). The residue was purified by reversephase column eluting with water (0.05% TFA)/ACN (85/15) to afford6-(5-amino-4-methylpyridin-3-yl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8-diamine(19.2 mg, 0.038 mmol) as an orange solid. LCMS (ESI) [M+H]⁺=456.2 .¹HNMR(400 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.10 (s, 1H), 7.99 (s, 1H), 7.70 (s,1H), 7.67 (s, 1H), 7.21 (d, J=1.2 Hz, 1H), 6.84 (d, J=1.2 Hz, 1H), 6.72(d, J=6.1 Hz, 1H), 6.05 (s, 3H), 5.40 (s, 2H), 5.22 (s, 2H), 4.39-4.31(m, 2H), 3.27-3.19 (m, 2H), 1.93 (s, 3H).

Example 1492-((6-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 249)

Step 1:2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of2-[[8-chloro-7-fluoro-6-(hydroxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.12 mmol) and thionyl chloride (70.6 mg, 0.60 mmol) indichloromethane (5 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum to afford2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.11 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=436.

Step 2:2-[[8-chloro-7-fluoro-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.11 mmol), 1H-pyrrolo[2,3-c]pyridine (40.62 mg, 0.34 mmol) andcesium carbonate (186.79 mg, 0.57 mmol) in N,N-dimethylformamide (6 mL)was stirred at 25° C. for 2 hours. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol (9/1)to afford2-[[8-chloro-7-fluoro-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(15 mg, 0.029 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=518.

Step 3: tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(70 mg, 0.14 mmol), tert-Butyl carbamate (474.33 mg, 4.05 mmol),tris(dibenzylideneacetone)dipalladium (27.97 mg, 0.03 mmol) andBrettphos (29.03 mg, 0.05 mmol) in 1,4-dioxane (10 mL) was added cesiumcarbonate (176.22 mg, 0.54 mmol) at 25° C. The resulting solution wasstirred for 2 hours at 90° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol (9/1)to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-8-isoquinolyl]carbamate(45 mg, 0.075 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=599.

Step 4:2-((6-((H-pyrrolo[2,3-c]pyridin-1-yl)methyl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A mixture of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-8-isoquinolyl]carbamate(80 mg, 0.13 mmol) in dichloromethane (4 mL) and 2,2,2-trifluoroaceticacid (4 mL) was stirred at 25° C. for 2 hours. The mixture wasconcentrated under vacuum. The residue was purified by prep-HPLC(Atlantis HILIC OBD, 19×150 mm 5 um; water (0.1% FA): CH₃CN=5%-6% B in 7min) to afford2-[[8-amino-7-fluoro-6-(pyrrolo[2,3-c]pyridin-1-ylmethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(9.4 mg, 0.017 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=499.3; ¹HNMR(300 MHz, DMSO-d₆) δ 9.17 (s, 1H), 9.08 (s, 1H), 8.96 (s, 1H), 8.12 (d,J=5.4 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H), 7.56 (s, 1H), 7.54 (d, J=1.0 Hz,1H), 6.74 (d, J=6.1 Hz, 1H), 6.57 (d, J=3.1 Hz, 1H), 6.06 (s, 2H), 5.95(s, 1H), 5.64 (s, 2H), 4.96 (s, 2H), 4.60 (t, J=6.8 Hz, 1H), 3.78 (s,2H), 2.98 (s, 2H), 1.13 (d, J=6.8 Hz, 6H).

Example 1502-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-7-methyl-6,7-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8(9H)-one(Compound 250)

Step 1: 2-[tert-butoxycarbonyl(methyl)amino]ethyl methanesulfonate

To a solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.0 g,5.71 mmol) and triethylamine (1.15 g, 11.41 mmol) in dichloromethane (20mL) was added dropwise methanesulfonyl chloride (975.86 mg, 8.56 mmol).The mixture was stirred at 0° C. for 1 hour. The resulting solution waswashed with water and the organic phase was dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum toafford 2-[tert-butoxycarbonyl(methyl)amino]ethyl methanesulfonate (1.29g, 5.08 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=254.

Step 2: tert-butylN-[2-(4-bromo-2-methyl-imidazol-1-yl)ethyl]-N-methyl-carbamate

A solution of 5-bromo-2-methyl-1H-imidazole (5.0 g, 31.06 mmol) andsodium hydride (1.86 g, 60% purity, 46.58 mmol) in N,N-dimethylformamide(100 mL) was stirred for 30 minutes at 0° C.2-[tert-Butoxycarbonyl(methyl)amino]ethyl methanesulfonate (8.0 g, 31.58mmol) was added and stirred at room temperature for 12 hours. Thereaction was quenched with water, extracted with ethyl acetate and driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% NH₃H₂O in water) to affordtert-butylN-[2-(4-bromo-2-methyl-imidazol-1-yl)ethyl]-N-methyl-carbamate (6 g,18.85 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=318.

Step 3: methyl2-[4-bromo-1-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]imidazol-2-yl]acetate

To a solution of tert-butylN-[2-(4-bromo-2-methyl-imidazol-1-yl)ethyl]-N-methyl-carbamate (2.0 g,6.29 mmol) and dimethyl carbonate (2.83 g, 31.43 mmol) intetrahydrofuran (100 mL) was added lithium diisopropylamide (7.54 mL,15.08 mmol, 2 mol/L) at −70° C. The resulting solution was stirred for 2hours at −70° C. to −30° C. The reaction was quenched with water. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified by reverse phase chromatography (acetonitrile 0-40/0.1% NH₃in water) to afford methyl2-[4-bromo-1-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]imidazol-2-yl]acetate(400 mg, 1.06 mmol) as a colorless solid. LCMS (ESI) [M+H]⁺=376.

Step 4: methyl 2-[4-bromo-1-[2-(methylamino)ethyl]imidazol-2-yl]acetate

A solution of methyl2-[4-bromo-1-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]imidazol-2-yl]acetate(400 mg, 1.06 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (3 mL) was stirred at 25° C. for 2 hours. The solventwas concentrated under vacuum to afford methyl2-[4-bromo-1-[2-(methylamino)ethyl]imidazol-2-yl]acetate (250 mg, 0.91mmol) as a colorless solid. LCMS (ESI) [M+H]⁺=276.

Step 5:2-bromo-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one

A solution of methyl2-[4-bromo-1-[2-(methylamino)ethyl]imidazol-2-yl]acetate (250 mg, 0.91mmol) and triethylamine (914.42 mg, 9.05 mmol) in methanol (10 mL) wasstirred at 25° C. for 12 hours. The solvent was concentrated undervacuum. The residue was purified by reverse phase chromatography(acetonitrile 0-40/0.1% NH₃ in water) to afford2-bromo-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one (160mg, 0.65 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=244.

Step 6:2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one

A mixture of2-bromo-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one (50mg, 0.20 mmol),8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (47.15 mg,0.16 mmol), t-BuBrettPhosG3 (69.97 mg, 0.08 mmol), t-BuBrettPhos (49.67mg, 0.10 mmol) and cesium carbonate (200.34 mg, 0.61 mmol) in1,4-dioxane (6 mL) was stirred at 120° C. for 3 hours. After filtration,the filtrate was concentrated under vacuum. The residue was purified byreverse phase chromatography (acetonitrile 0-40/0.1% NH₄CO₃ in water) toafford2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one(5.7 mg, 0.013 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=451.

Step 7: tert-butyl(7-fluoro-3-((7-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-d][1,4]diazepin-2-yl)amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a mixture of2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one(230 mg, 0.51 mmol), tert-butyl carbamate (1.79 g, 15.3 mmol),tris(dibenzylideneacetone)dipalladium (105.59 mg, 0.10 mmol) andBrettphos (109.57 mg, 0.20 mmol) in 1,4-dioxane (15 mL) was added cesiumcarbonate (665.16 mg, 2.04 mmol) at 25° C. The reaction was stirred for1 hour at 90° C. After filtration, the filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (9/1) to afford tert-butylN-[7-fluoro-3-[(7-methyl-8-oxo-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-2-yl)amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(70 mg, 0.13 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=532.

Step 8:2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one

A solution of tert-butylN-[7-fluoro-3-[(7-methyl-8-oxo-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-2-yl)amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(65 mg, 0.12 mmol) in dichloromethane (5 mL) and 2,2,2-trifluoroaceticacid (5 mL) was stirred at 25° C. for 2 hours. The solvent wasconcentrated under vacuum. The residue was purified by prep-HPLC(Atlantis HILIC OBD, 19×150mm 5 um; water (0.1% FA): CH₃CN=7%-10% B in 7min) to afford2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-7-methyl-6,9-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8-one(2 mg, 0.0042 mmol,) as a red solid. LCMS (ESI) [M+H]⁺=432.2; ¹H NMR(400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.87 (s, 1H), 8.49 (d, J=5.0 Hz, 1H),8.41 (s, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.07 (d, J=19.2 Hz, 2H), 6.70 (d,J=6.1 Hz, 1H), 6.10 (s, 2H), 4.11 (d, J=5.8 Hz, 2H), 3.99 (d, J=5.4 Hz,2H), 3.89 (s, 2H), 2.96 (s, 3H), 2.21 (s, 3H).

Example 1512-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,5-dihydro-7H-pyrazolo[1,5-c][1,3]thiazine6,6-dioxide (Compound 252)

Step 1: ethyl 2-(chloromethylsulfanyl)acetate

To a solution of sodium hydride (5.83 g, 60% purity, 145.63 mmol) intetrahydrofuran (200 mL) was added ethyl 2-mercaptoacetate (17.5g,145.63 mmol) at 0° C. The resulting solution was stirred for 30 minutesat 0° C. Bromochloromethane (94.21 g, 728.14 mmol) was added and stirredat 0° C. for 2 hours. After filtration, the filtrate was concentratedunder vacuum. The crude product was distilled in vacuo to afford ethyl2-(chloromethylsulfanyl)acetate (14 g, 83.02 mmol) as a colorless oil.GCMS=168.

Step 2: methyl5-bromo-2-[(2-ethoxy-2-oxo-ethyl)sulfanylmethyl]pyrazole-3-carboxylate

To a mixture of methyl 5-bromo-1H-pyrazole-3-carboxylate (1.5 g, 7.32mmol), ethyl 2-(chloromethylsulfanyl)acetate (1.36 g, 8.05 mmol) andpotassium carbonate (2.02 g, 14.63 mmol) in N,N-dimethylformamide (30mL) was added tetrabutylammonium iodide (134.99 mg, 0.37 mmol) at 25° C.The resulting solution was stirred for 4 hours at 25° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (5/1) to afford methyl5-bromo-2-[(2-ethoxy-2-oxo-ethyl)sulfanylmethyl]pyrazole-3-carboxylate(1.8 g, 5.34 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=337.

Step 3: methyl2-bromo-4-oxo-7H-pyrazolo[1,5-c][1,3]thiazine-5-carboxylate

A solution of methyl5-bromo-2-[(2-ethoxy-2-oxo-ethyl)sulfanylmethyl]pyrazole-3-carboxylate(500 mg, 1.48 mmol) and sodium methylate (0.55 mL, 2.97 mmol) inmethanol (10 mL) was stirred at 25° C. for 4 hours. The reaction mixturewas adjusted to pH 8 with acetic acid. The solvent was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (5/1) to afford methyl2-bromo-4-oxo-7H-pyrazolo[1,5-c][1,3]thiazine-5-carboxylate (270 mg,0.93 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=291.

Step 4: 2-bromo-7H-pyrazolo[1,5-c][1,3]thiazin-4-one

A solution of methyl2-bromo-4-oxo-7H-pyrazolo[1,5-c][1,3]thiazine-5-carboxylate (1.1 g, 3.78mmol) and concentrated sulfuric acid (49.37 g, 75.57 mmol) in1,4-dioxane (15 mL) was stirred at 100° C. for 12 hours. The reactionmixture was adjusted to pH 6 with sodium hydroxide (10%). The resultingsolution was extracted with ethyl acetate, dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum toafford 2-bromo-7H-pyrazolo[1,5-c][1,3]thiazin-4-one (900 mg, 2.90 mmol)as a yellow solid. LCMS (ESI) [M+H]⁺=233.

Step 5:N-[(Z)-(2-bromo-7H-pyrazolo[1,5-c][1,3]thiazin-4-ylidene)amino]-4-methyl-benzenesulfonamide

A solution of 2-bromo-7H-pyrazolo[1,5-c][1,3]thiazin-4-one (50 mg, 0.21mmol) and 4-methylbenzenesulfonohydrazide (39.95 mg, 0.21 mmol) inmethanol (3 mL) was stirred at 25° C. for 12 hours. The solvent wasconcentrated under vacuum. The solid was washed with petroleum ether (10mL) to affordN-[(Z)-(2-bromo-7H-pyrazolo[1,5-c][1,3]thiazin-4-ylidene)amino]-4-methyl-benzenesulfonamide(80 mg, 0.20 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=401.

Step 6: 2-bromo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine

To a solution ofN—[(Z)-(2-bromo-7H-pyrazolo[1,5-c][1,3]thiazin-4-ylidene)amino]-4-methyl-benzenesulfonamide(80 mg, 0.20 mmol) in dichloromethane (10 mL) was addeddiisobutylaluminium hydride (1 mL, 1.0 mmol, 1 mol/L) at 0° C. Theresulting solution was stirred 1 hour at 0° C. The reaction was quenchedwith water and then extracted with ethyl acetate. The organic layerswere combined, dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum. The residue was purified byreverse phase chromatography (acetonitrile 0-40/0.1% sodium bicarbonatein water) to afford 2-bromo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine(20 mg, 0.091 mmol) as a white solid. LCMS (ESI) [M+H]⁺=219.

Step 7: 2-bromo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide

A solution of 2-bromo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine (130mg, 0.59 mmol) and 3-chloroperoxybenzoic acid (612.32 mg, 3.56 mmol) indichloromethane (10 mL) was stirred at 25° C. for 3 hours. The reactionwas quenched with sodium sulfite and sodium bicarbonate solution. Theresulting solution was extracted with ethyl acetate, dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The resulting residue was purified by reversephase chromatography (acetonitrile 0-40/0.1% HCl in water) to afford2-bromo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide (70 mg,0.28 mmol) as a white solid. LCMS (ESI) [M+H]⁺=251.

Step 8: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

To a mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(250 mg, 0.50 mmol), 2-bromo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine6,6-dioxide (149.77 mg, 0.60 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (102.89 mg, 0.10mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.12 mg,0.20 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (486.11 mg,1.49 mmol) at 25° C. The resulting solution was stirred for 2 hours at100° C. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith petroleum ether/ethyl acetate (2/3) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(70 mg, 0.10 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=673.

Step 9: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

To a mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(65 mg, 0.10 mmol), tert-Butyl carbamate (339.36 mg, 2.90 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (19.99 mg, 0.020mmol) and Brettphos (20.74 mg, 0.040 mmol) in 1,4-dioxane (10 mL) wasadded cesium carbonate (125.92 mg, 0.39 mmol) at 25° C. The resultingsolution was stirred for 4 hours at 90° C. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(60 mg, 0.080 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=754.

Step 10:6-(5-amino-4-methyl-3-pyridyl)-N3-(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)-7-fluoro-isoquinoline-3,8-diamine

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxymethylamino)-3-[(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(53.98 mg, 0.070 mmol) in dichloromethane (2 mL) and2,2,2-trifluoroacetic acid (2 mL) was stirred at 25° C. for 2 hours. Thesolvent was concentrated under vacuum. The crude product was purified byprep-HPLC (Atlantis HILIC OBD, 19×150mm 5 um; water (0.1% FA):CH₃CN=3%-15% B in 7 min) to afford6-(5-amino-4-methyl-3-pyridyl)-N3-(6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)-7-fluoro-isoquinoline-3,8-diamine(5.5 mg, 0.011 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=454.2; ¹HNMR(300 MHz, DMSO-d₆) δ 9.33 (s, 1H), 9.30 (s, 1H), 8.00 (s, 1H), 7.87 (s,1H), 7.71 (s, 1H), 6.70 (d, J=6.0 Hz, 1H), 6.18 (s, 2H), 6.08 (s, 1H),5.82 (s, 2H), 5.43 (s, 2H), 3.58 (t, J=6.6 Hz, 2H), 3.27 (t, J=6.6 Hz,2H), 2.00 (d, J=1.5 Hz, 3H).

Example 1522-((8-amino-6-cyclopropyl-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 253)

Step 1: tert-butyl6-cyclopropyl-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-8-ylcarbamate

To a mixture of8-(tert-butoxycarbonylamino)-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-6-yltrifluoromethanesulfonate (150 mg, 0.24 mmol), cyclopropylboronic acid(41.88 mg, 0.49 mmol) and tetrakis(triphenylphosphine)palladium (56.20mg, 0.049 mmol) in 1,4-dioxane (5 mL) was added potassium carbonate(84.01 mg, 0.61 mmol) at 25° C. The resulting solution was stirred for 3hours at 100° C. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (9/1) to affordtert-butyl6-cyclopropyl-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-8-ylcarbamate(100 mg, 0.20 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=509.

Step 2:2-[(8-amino-6-cyclopropyl-7-fluoro-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[6-cyclopropyl-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(70 mg, 0.14 mmol) in 2,2,2-trifluoroacetic acid (4 mL) was stirred at25° C. for 2 hours. The solvent was concentrated under vacuum. The crudeproduct was purified by prep-HPLC (Atlantis HILIC OBD, 19×150 mm 5 um;water (10 mmol/L sodium bicarbonate): CH₃CN=33%-50% B in 10 min) toafford2-[(8-amino-6-cyclopropyl-7-fluoro-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(8.4 mg, 0.021 mmol) as a red solid. LCMS (ESI) [M+H]⁺=409.2; ¹HNMR (300MHz, DMSO-d₆) δ 9.12 (s, 1H), 7.47 (s, 1H), 6.48 (d, J=6.3 Hz, 1H), 5.97(s, 1H), 4.95 (s, 2H), 4.64-4.53 (m, 1H), 3.76 (t, J=6.0 Hz, 2H), 3.00(t, J=6.0 Hz, 2H), 2.13-2.09 (m, 1H), 1.14 (d, J=6.9 Hz, 6H), 1.06-0.96(m, 2H), 0.84-0.82 (m, 2H).

Example 153 and Example 1542-((8-amino-7-fluoroisoquinolin-3-yl)amino)-6-i sopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Compound 254) and2-((8-amino-7-fluoro-6-(2-isopropoxy-4-methylpyrimidin-5-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 255)

Step 1: 5-bromo-2-isopropoxy-4-methylpyrimidine

Sodium hydride (550 mg, 60% purity, 13.75 mmol) was added batchwise intoa solution of 2-propanol (1.75 g, 29.12 mmol) in tetrahydrofuran (50 mL)at 0° C. The resulting solution was stirred for 30 minutes at roomtemperature. 5-Bromo-2-chloro-4-methylpyrimidine (1.0 g, 4.82 mmol) wasadded at 0° C. The resulting solution was stirred for 16 hours at roomtemperature. The mixture was diluted with brine. The resulting solutionwas extracted with ethyl acetate, dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withpetroleum ether/dichloromethane (2/1) to afford5-bromo-2-isopropoxy-4-methyl-pyrimidine (350 mg, 1.51 mmol) as lightyellow oil. LCMS (ESI) [M+H]⁺=231.

Step 2:2-isopropoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

A mixture of bis(pinacolato)diboron (2.043 g, 8.05 mmol),5-bromo-2-isopropoxy-4-methyl-pyrimidine (310 mg, 1.34 mmol), potassiumacetate (394.39 mg, 4.02 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (98.2 mg,0.13 mmol) in 1,4-dioxane (50 mL) was stirred at 80° C. for 15 hours.The mixturewas concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with petroleumether/dichloromethane (3/7) to afford2-isopropoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(350 mg, 1.26 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=279.

Step 3: tert-butyl(7-fluoro-6-(2-isopropoxy-4-methylpyrimidin-5-yl)-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-8-yl)carbamateand tert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-8-yl)carbamate

A solution of[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate(150 mg, 0.24 mmol),2-isopropoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(101.5 mg, 0.36 mmol), terakis(triphenylphosphine)palladium (56.2 mg,0.05 mmol) and potassium carbonate (100.72 mg, 0.73 mmol) in 1,4-dioxane(10 mL) and water (1 mL) was stirred at 90° C. for 2 hours. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butylN-[7-fluoro-6-(2-isopropoxy-4-methyl-pyrimidin-5-yl)-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(35 mg, 0.057 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=619. Andtert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-8-yl)carbamate(20 mg, 0.042 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=469.

Step 4:2-((8-amino-7-fluoro-6-(2-isopropoxy-4-methylpyrimidin-5-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 255)

A solution of tert-butylN-[7-fluoro-6-(2-isopropoxy-4-methyl-pyrimidin-5-yl)-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(30 mg, 0.05 mmol) and TFA (5 mL) in dichloromethane (1 mL) was stirredat 25° C. for 1 hour. The mixture was concentrated under vacuum. Thereaction was adjusted to pH 10 with ammonia in methanol (7 mol/L). Thecrude product was purified by Prep-HPLC (XBridge Shield RP18 OBD Column30*150 mm, 5 um; Water (10 mmol/L sodium bicarbonate): ACN (32%-60%) in8 min; 60 mL/min) to afford2-[[8-amino-7-fluoro-6-(2-isopropoxy-4-methyl-pyrimidin-5-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(7.7 mg, 0.015 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=519.3; ¹HNMR(300 MHz, Methanol-d₄) δ 9.15 (s, 1H), 8.41 (s, 1H), 7.66 (s, 1H), 6.89(d, J=6.0 Hz, 1H), 6.05 (s, 1H), 5.49-5.34 (m, 1H), 5.06 (s, 2H),4.89-4.71 (m, 1H), 3.97-3.80 (m, 2H), 3.24-3.06 (m, 2H), 2.41 (s, 3H),1.44 (d, J=6.2 Hz, 6H), 1.24 (d, J=6.8 Hz, 6H).

Step 5:2-((8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 254)

A solution of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(20 mg, 0.04 mmol) and 2,2,2-trifluoroacetic acid (4 mL) was stirred at25° C. for 1 hour. The mixture was concentrated under vacuum. Thereaction mixture was adjusted to pH 10 with ammonia in methanol (7mol/L). The crude product was purified by Prep-HPLC (SunFire Prep C18OBD Column 19×150 mm 5 um; Water (0.1% FA): ACN (25%-52%) in 7 min; 25mL/min) to afford2-[(8-amino-7-fluoro-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(2.5 mg, 0.0068 mmol) as a orange solid. LCMS (ESI) [M+H]⁺=369.2; ¹HNMR(300 MHz, Methanol-d₄) δ 9.23 (s, 1H), 7.55 (s, 1H), 7.51-7.42 (m, 1H),7.06-7.02 (m, 1H), 5.99 (s, 1H), 5.14 (s, 2H), 4.83-4.72 (m, 1H),3.96-3.85 (m, 2H), 3.18-3.05 (m, 2H), 1.25 (d, J=6.8 Hz, 6H).

Example 1552-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-isopropyl-4,5-dihydro-7H-pyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide (Compound 256)

Step 1: 1-chloro-N-isopropyl-methanesulfonamide

A mixture of isopropylamine (1.19 g, 20.13 mmol) and triethylamine (2.03g, 20.13 mmol) in dichloromethane (100 mL) was added chloromethanesulfonylchloride (1.5 g, 10.07 mmol) at 0° C. The reaction was stirredfor 2 hours at 0° C. The resulting solution was washed with water. Theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum to afford1-chloro-N-isopropyl-methanesulfonamide (1.1 g, 6.40 mmol) as colorlessoil. GCMS=171.

Step 2: methyl5-bromo-2-(isopropylsulfamoylmethyl)pyrazole-3-carboxylate

A mixture of 1-chloro-N-isopropyl-methanesulfonamide (1381.51 mg, 8.05mmol) methyl 3-bromo-1H-pyrazole-5-carboxylate (1.1 g, 5.37 mmol) andpotassium carbonate (2.22 g, 16.1 mmol) in 1-methyl-2-pyrrolidinone (20mL) was stirred at 60° C. for 5 hours. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byreverse phase chromatography (acetonitrile 0-40/0.1% NH₃H₂O in water) toafford methyl 5-bromo-2-(isopropylsulfamoylmethyl)pyrazole-3-carboxylate (600 mg, 1.76 mmol) as a white solid. LCMS (ESI)[M+H]⁺=340.

Step 3:1-[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]-N-isopropyl-methanesulfonamide

To a solution of methyl5-bromo-2-(isopropylsulfamoylmethyl)pyrazole-3-carboxylate (600 mg, 1.76mmol) in dichloromethane (20 mL) was added diisobutylaluminium hydride(3.53 mL, 3.53 mmol, 1 mol/L) at 0° C. The resulting solution wasstirred for 2 hours at 0° C. The reaction was quenched with methanol.After filtration, the filtrate was concentrated under reduced pressure.The resulting residue was purified by reverse phase chromatography(acetonitrile 0-40/0.1% sodium bicarbonate in water) to afford1-[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]-N-isopropyl-methanesulfonamide(400 mg, 1.28 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=312.

Step 4: 2-bromo-5-isopropyl-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide

A solution of1-[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]-N-isopropyl-methanesulfonamide(400 mg, 1.28 mmol) and triphenylphosphine (671 mg, 2.56 mmol) intetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (517 mg,2.56 mmol) at 0° C. under nitrogen. The resulting solution was stirredfor 2 hours at room temperature. The organic layer was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (7/3) to afford2-bromo-5-isopropyl-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide (300 mg, 1.02 mmol) as a white solid. LCMS (ESI) [M+H]⁺=294.

Step 5: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(342 mg, 0.68 mmol),2-bromo-5-isopropyl-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide (200 mg, 0.68 mmol)tris(dibenzylideneacetone)dipalladium-chloroformadduct (140 mg, 0.14mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (157.19 mg, 0.27mmol), cesium carbonate (665 mg, 2.04 mmol) in 1,4-dioxane (20 mL) wasstirred under nitrogen for 6 hours at 100° C. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (2/3) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(105 mg, 0.15 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=716.

Step 6: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(90 mg, 0.13 mmol), tert-butyl carbamate (294.42 mg, 2.51 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (26 mg, 0.03mmol), Brettphos (27 mg, 0.05 mmol) and cesium carbonate (122 mg, 0.38mmol) in 1,4-dioxane (10 mL) was stirred for 2 hours at 90° C. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withpetroleum ether/ethyl acetate (2/3) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(60 mg, 0.075 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=797.

Step 7:6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)isoquinoline-3,8-diamine;formic acid

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(60 mg, 0.08 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (4 mL) was stirred at 25° C. for 2 hours. The solventwas concentrated under vacuum. The resulting residue was purified byreverse phase chromatography (acetonitrile 0-40/0.1% FA in water) toafford 6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(5-isopropyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)isoquinoline-3,8-diamine; formic acid (18.6 mg, 0.034mmol) as a orange solid. LCMS (ESI) [M+H]⁺=497; ¹HNMR (400 MHz, CD₃OD) δ9.17 (s, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.77 (s, 1H), 6.85 (d, J=6.4Hz, 1H), 6.13 (s, 1H), 5.28 (s, 2H), 4.63 (s, 2H), 4.34-4.27 (m, 1H),2.08 (s, 3H), 1.20 (d, J=6.4 Hz, 6H).

Example 1562-((8-amino-6-(benzyloxy)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 257)

A solution of tert-butylN-[6-benzyloxy-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(50 mg, 0.086 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (5 mL) was stirred at 25° C. for 3 hours. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH 7with ammonia in methanol (7 mol/L). The residue was purified by flashchromatography on C18 (acetonitrile-0.1% sodium bicarbonate in water) toafford2-((8-amino-6-(benzyloxy)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(12.2 mg, 0.026 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=475.2. ¹H NMR(300 MHz, DMSO-d₆) δ 9.02 (d, J=14.0 Hz, 2H), 7.60 (s, 1H), 7.56-7.46(m, 2H), 7.50-7.31 (m, 3H), 6.62-6.59 (m, 1H), 5.94 (d, J=6.4 Hz, 3H),5.25 (s, 2H), 4.98 (s, 2H), 4.63-4.58 (m, 1H), 3.79-3.77 (m, 2H),3.00-2.98 (m, 2H), 1.13 (d, J=6.8 Hz, 6H).

Example 1572-((8-amino-7-fluoro-6-methylisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 258)

Step 1: tert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-6-methylisoquinolin-8-yl)carbamate

A solution of[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate (100 mg, 0.16 mmol), trimethylboroxine (101.79mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium (37.46 mg, 0.03mmol) and potassium carbonate (67.14 mg, 0.49 mmol) was stirred at 90°C. for 2 hours. The solvent was concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-methyl-8-isoquinolyl]carbamate(35 mg, 0.073 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=483.

Step2:2-((8-amino-7-fluoro-6-methylisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-methyl-8-isoquinolyl]carbamate(25 mg, 0.05 mmol) and 2,2,2-trifluoroacetic acid (5 mL) was stirred at25° C. for 1 hour. The reaction was concentrated under vacuum. Theresidue was adjusted to pH 10 with ammonia in methanol (7 mol/L). Thecrude product was purified by Prep-HPLC (SunFire Prep C18 OBD Column19×150 mm 5 um 10 nm; Water (0.1%FA): ACN (10%-27%) in 12 min: 25mL/min) to afford2-[(8-amino-7-fluoro-6-methyl-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(5.4 mg, 0.014 mmol) as a orange solid. LCMS (ESI) [M+H]⁺=383.2; ¹HNMR(300 MHz, Methanol-d₄) δ 9.03 (s, 1H), 7.53 (s, 1H), 6.85 (d, J=6.6 Hz,1H), 6.03 (s, 1H), 5.07 (s, 2H), 4.83-4.65 (m, 1H), 3.96-3.81 (m, 2H),3.24-3.08 (m, 2H), 2.39 (d, J=2.3 Hz, 3H), 1.25 (d, J=6.8 Hz, 6H).

Example 1582-((8-amino-7-fluoro-6-methoxyisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 259)

Step 1: tert-butyl(7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-6-methoxyisoquinolin-8-yl)carbamate

A solution of tert-butylN-[7-fluoro-6-hydroxy-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(100 mg, 0.21 mmol) and potassium carbonate (42.72 mg, 0.31 mmol) inN,N-dimethylformamide (10 mL) was stirred at 0° C. for 15 minutes. Theniodomethane (43.96 mg, 0.31 mmol) was added and then stirred at 0° C.for 2 hours. After filtration, the filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (20/1) to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-methoxy-8-isoquinolyl]carbamate(58 mg, 0.12 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=499

Step 2:2-((8-amino-7-fluoro-6-methoxyisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-methoxy-8-isoquinolyl]carbamate(55 mg, 0.11 mmol) and 2,2,2-trifluoroacetic acid (0.5 mL) indichloromethane (2 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum. The reaction mixture was adjusted to pH 10with ammonia in methanol (7 mol/L).The crude product was purified byPrep-HPLC (XBridge Shield RP18 OBD Column 30*150 mm, 5 um ; Water (10mmol/L sodium bicarbonate): ACN (20%-46%) in 9 min: 60 mL/min) to afford2-[(8-amino-7-fluoro-6-methoxy-3-isoquinolyl)amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(17.2 mg, 0.043 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=399.2; ¹HNMR(300 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.97 (s, 1H), 7.62 (s, 1H), 6.48 (d,J=7.2 Hz, 1H), 5.95 (s, 2H), 5.89 (s, 1H), 4.98 (s, 2H), 4.62-4.57 (m,1H), 3.90 (s, 3H), 3.80-3.76 (m, 2H), 2.99-2.96 (m, 2H), 1.13 (d, J=6.8Hz, 6H).

Example 1592-((8-amino-7-fluoro-6-((pyridin-2-yloxy)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 260)

Step 1:2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of2-[[8-chloro-7-fluoro-6-(hydroxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(145 mg, 0.35 mmol) and thionyl chloride (204.73 mg, 1.74 mmol) indichloromethane (5 mL) was stirred at 25° C. for 1 hour. The solvent wasconcentrated under vacuum to afford2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.34 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=436.

Step 2:2-((8-chloro-7-fluoro-6-((pyridin-2-yloxy)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-oneand2-[[8-chloro-7-fluoro-6-[(2-oxo-1-pyridyl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-[[8-chloro-6-(chloromethyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.34 mmol), 1H-pyridin-2-one (98.08 mg, 1.03 mmol) and cesiumcarbonate (560.38 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) wasstirred at 25° C. for 4 hours. After filtration, the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby reverse phase chromatography (acetonitrile 0-40/0.1% hydrochloricacid in water) to afford2-((8-chloro-7-fluoro-6-((pyridin-2-yloxy)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(15 mg, 0.03 mmol) and2-[[8-chloro-7-fluoro-6-[(2-oxo-1-pyridyl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(85 mg, 0.17 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=495.

Step 3: tert-butyl7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)-6-((pyridin-2-yloxy)methyl)isoquinolin-8-ylcarbamate

To a mixture of2-(8-chloro-7-fluoro-6-((pyridin-2-yloxy)methyl)isoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(14 mg, 0.028 mmol), tert-butyl carbamate (99.47 mg, 0.85 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (5.86 mg, 0.0057mmol) and Brettphos (6.08 mg, 0.011 mmol) in 1,4-dioxane (3 mL) wasadded cesium carbonate (36.9 mg, 0.11 mmol) at 25° C. The resultingsolution was stirred for 3 hours at 90° C. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (9/1) to afford tert-butyl7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)-6-((pyridin-2-yloxy)methyl)isoquinolin-8-ylcarbamate(15 mg, 0.076 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=576.

Step 4:2-[[8-amino-7-fluoro-6-(2-pyridyloxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(2-pyridyloxymethyl)-8-isoquinolyl]carbamate(18 mg, 0.03 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroaceticacid (2 mL) was stirred at 25° C. for 2 hours. The solvent wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Atlantis HILIC OBD, 19×150 mm 5 um; water (10 mmol/sodium bicarbonate):CH₃CN=35%-55% B in 7 min) to afford2-[[8-amino-7-fluoro-6-(2-pyridyloxymethyl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(3.4 mg, 0.0072 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=476.2; ¹HNMR(400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 9.06 (s, 1H), 8.20 (ddd, J=5.1, 2.0,0.8 Hz, 1H), 7.76 (ddd, J=8.4, 7.1, 2.0 Hz, 1H), 7.64 (s, 1H), 7.02(ddd, J=7.1, 5.0, 1.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.01 (s, 2H), 5.96 (s,1H), 5.45 (s, 2H), 4.96 (s, 2H), 4.59 (q, J=6.8 Hz, 1H), 3.78 (t, J=5.9Hz, 2H), 2.98 (t, J=5.9 Hz, 2H), 1.12 (d, J=6.8 Hz, 6H).

Example 1602-((8-amino-7-fluoro-6-((2-oxopyridin-1(2H)-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 261)

Step 1: tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-[(2-oxo-1-pyridyl)methyl]-8-isoquinolyl]carbamate

A solution of2-[[8-chloro-7-fluoro-6-[(2-oxo-1-pyridyl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(95 mg, 0.19 mmol), tert-butyl carbamate (673.7 mg, 5.76 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (39.73 mg, 0.040mmol) and Brettphos (41.23 mg, 0.080 mmol) in 1,4-dioxane (10 mL) wasadded cesium carbonate (250.29 mg, 0.77 mmol) at 25° C. The resultingsolution was stirred for 3 hours at 90° C. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-[(2-oxo-1-pyridyl)methyl]-8-isoquinolyl]carbamate(75 mg, 0.13 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=576

Step 2:2-[[8-amino-7-fluoro-6-[(2-oxo-1-pyridyl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-[(2-oxo-1-pyridyl)methyl]-8-isoquinolyl]carbamate(70 mg, 0.12 mmol) in 2,2,2-trifluoroacetic acid (3 mL) anddichloromethane (5 mL) was stirred at 25° C. for 2 hours. The solventwas concentrated under vacuum. The crude product was purified byPrep-HPLC (Atlantis HILIC OBD, 19×150 mm 5 um; water (10 mmol/sodiumbicarbonate): CH₃CN=13%-43% B in 7 min) to afford2-[[8-amino-7-fluoro-6-[(2-oxo-1-pyridyl)methyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(23.8 mg, 0.050 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=476.2; ¹HNMR(400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 9.06 (s, 1H), 7.72 (dd, J=6.9, 2.0Hz, 1H), 7.53-7.43 (m, 2H), 6.49-6.39 (m, 2H), 6.29 (td, J=6.7, 1.4 Hz,1H), 6.05 (s, 2H), 5.96 (s, 1H), 5.20 (s, 2H), 4.94 (s, 2H), 4.59 (m,J=6.8 Hz, 1H), 3.77 (t, J=5.9 Hz, 2H), 2.97 (t, J=5.9 Hz, 2H), 1.11 (d,J=6.8 Hz, 6H).

Example 1616-(5-amino-4-methylpyridin-3-yl)-N3-(7,7-difluoro-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-c]azepin-2-yl)-7-fluoroisoquinoline-3,8-diamine(Compound 262)

Step 1: 1-(3,5-dibromopyrazol-1-yl)hex-5-en-2-ol

A solution of 3,5-dibromo-1H-pyrazole(5.0 g, 22.14 mmol),1,2-epoxy-5-hexene (4.35 g, 44.27 mmol) and cesium carbonate(21.78 g,66.41 mmol) in N,N-dimethylformamide(20 mL) was stirred at 85° C. for 2hours. The solvent was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (3/1) to afford1-(3,5-dibromopyrazol-1-yl)hex-5-en-2-ol(4.2 g, 13.0 mmol) as a lightyellow oil. LCMS (ESI) [M+H]⁺=324.0.

Step 2: 2-bromo-4-methylene-5,6,7,8-tetrahydropyrazolo[1,5-a]azepin-7-ol

A mixture of [1-(3,5-dibromopyrazol-1-yl)hex-5-en-2-ol (7.2 g, 22.22mmol), palladium acetate (500 mg, 2.23 mmol), triphenylphosphine (1170.0mg, 4.47 mmol), potassium acetate (6570.0 mg, 67.04 mmol) andtetrabutylammonium bromide (7155.33 mg, 22.22 mmol)] inN,N-dimethylacetamide (70 mL) at 90° C. for 12 hours under nitrogen.After filtration, filtrate was concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting withpetroleum ether/ethyl acetate (2/1) to afford2-bromo-4-methylene-5,6,7,8-tetrahydropyrazolo[1,5-a]azepin-7-ol (3.8 g,15.63 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=243.1.

Step 3: 2-bromo-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepin-7-one

A mixture of2-bromo-4-methylene-5,6,7,8-tetrahydropyrazolo[1,5-a]azepin-7-ol (1.5 g,6.17 mmol) and DMP in dichloromethane (20 mL) was stirred at 25° C. for3 hours. The reaction mixture was adjusted to pH 7 with sodiumbicarbonate in water. The resulting solution was extracted withdichloromethane, dried with anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with petroleum ether/ethylacetate (4/1) to afford2-bromo-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepin-7-one (600 mg,2.49 mmol) as a yellow oil. LC/MS (ESI) [M+H]⁺=241.1.

Step 4:2-bromo-7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepine

A solution of2-bromo-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepin-7-one (400 mg,1.66 mmol) and diethylaminosulfur trifluoride (801.39 mg, 4.98 mmol) indichloromethane (10 mL) was stirred at 0° C. for 1 hour. The mixture wasquenched by water. The resulting solution was extracted with ethylacetate, dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with petroleum ether/ethylacetate (5/1) to afford2-bromo-7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepine(120 mg, 0.46 mmol) as a light yellow oil. LC/MS (ESI): [M+H]⁺=263.1.

Step 5: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepine(21.24 mg, 0.08 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(65.0 mg, 0.13 mmol), t-BuBrettphosPdG3 (44.15 mg, 0.05 mmol),t-BuBrettphos (31.27 mg, 0.06 mmol) and cesium carbonate (126.39 mg,0.39 mmol) in 1,4-dioxane (6 mL) was stirred at 130° C. for 2 hours. Thesolvent was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with PE/EA(1/1) to affordtert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-c]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(30 mg, 0.044 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=685.1.

Step 6: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-c]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-c]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(40 mg, 0.06 mmol), tert-butyl carbamate (170.99 mg, 1.46 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (12.09 mg, 0.01mmol), Brettphos (9.39 mg, 0.02 mmol) and cesium carbonate (57.1 mg,0.18 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 3 hours. Thesolvent was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-c]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(40 mg, 0.06 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=765.8.

Step 7: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-difluoro-4-methyl-4,5,6,8-tetrahydropyrazolo[1,5-a]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-difluoro-4-methylene-6,8-dihydro-5H-pyrazolo[1,5-a]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(105.0 mg, 0.14 mmol) and palladium carbon (10%) (20 mg, 0.14 mmol) inmethanol (5 mL) was stirred at 25° C. for 1 hour. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-difluoro-4-methyl-4,5,6,8-tetrahydropyrazolo[1,5-a]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(70 mg, 0.09 mmol) as a light yellow solid. LC/MS (ESI) [M+H]⁺=767.8.

Step 8:6-(5-amino-4-methylpyridin-3-yl)-N3-(7,7-difluoro-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)-7-fluoroisoquinoline-3,8-diamine

A solution of [tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-difluoro-4-methyl-4,5,6,8-tetrahydropyrazolo[1,5-a]azepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(70 mg, 0.09 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (5 mL) was stirred at 25° C. for 2 hours. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH 7with ammonia in methanol (7 mol/L). The residue was purified by lashchromatography on C18 (acetonitrile-0.1% FA in water) to afford6-(5-amino-4-methylpyridin-3-yl)-N3-(7,7-difluoro-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)-7-fluoroisoquinoline-3,8-diamine(19.9 mg, 0.043 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=486.2. ¹HNMR(300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.14 (s, 1H), 8.01 (s, 1H), 7.77 (s,1H), 7.73 (s, 1H), 6.75 (d, J=6.1 Hz, 1H), 6.13 (s, 2H), 5.94 (s, 1H),5.55 (s, 2H), 4.77-4.65 (m, 1H), 4.48-4.35 (m, 1H), 3.04-2.95 (m, 1H),2.40-2.20(m, 2H) 1.99 (s, 3H), 1.82 (d, J=14.4 Hz, 1H), 1.50-1.40 (m,1H), 1.32 (d, J=6.9 Hz, 3H).

Example 1625-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-1-methyl-1,3-dihydroisothiazolo[4,3-b]pyridine2,2-dioxide (Compound 263)

Step 1: N-(2,6-dichloro-3-pyridyl)methanesulfonamide

A solution of 2,6-dichloro-3-pyridinylamine (3.0 g, 18.4 mmol),triethylamine (9.29 g, 92.02 mmol) and methanesulfonyl chloride (6.29 g,55.21 mmol) in dichloromethane (120 mL) was stirred at 0° C. for 2hours. The reaction mixture was adjusted to pH 10 with 10% sodiumhydroxide solution. The resulting mixture was stirred at 20° C. for 1hour. The resulting mixture was extracted with dichloromethane andaqueous layers were combined. The reaction mixture was adjusted to pH 5with 12% hydrochloric acid solution. After filtration, the solids werecollected and dried to affordN-(2,6-dichloro-3-pyridyl)methanesulfonamide (3 g, 12.44 mmol) as acolorless solid. LCMS (ESI) [M+H]⁺=241.1.

Step 2: N-(2,6-dichloro-3-pyridyl)-N-methyl-methanesulfonamide

A solution of N-(2,6-dichloro-3-pyridyl)methanesulfonamide (3.5 g, 14.52mmol), potassium carbonate (5.01 g, 36.29 mmol), tetrabutylammoniumbromide (0.93 g, 2.9 mmol) and iodomethane (6.18 g, 43.55 mmol) inN,N-dimethylformamide (170 mL) was stirred at 20° C. for 3 hours. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by a reversed-phase chromatography (C18 silica gel;0.5% sodium bicarbonate in water:ACN (5%˜70%) in 30 min) to affordN-(2,6-dichloro-3-pyridyl)-N-methyl-methanesulfonamide (3.5 g, 13.72mmol) as a red oil. LC/MS (ESI): [M+H]⁺=255.1.

Step 3: 5-chloro-1-methyl-3H-isothiazolo[4,3-b]pyridine 2,2-dioxide

To a solution of N-(2,6-dichloro-3-pyridyl)-N-methyl-methanesulfonamide(2.2 g, 8.62 mmol) and potassium tert-butoxide (2.41 g, 21.56 mmol) indimethyl sulfoxide (70 mL) was stirred at 20° C. for 2 hours. Afterfiltration, the reaction system was purified by a reversed-phasechromatography (C18 silica gel; 0.5% sodium bicarbonate inwater:methanol (5%˜45%) in 30 min) to afford5-chloro-1-methyl-3H-isothiazolo[4,3-b]pyridine 2,2-dioxide (900 mg,4.12 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=218.7.

Step 4: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(300 mg, 0.60 mmol), 5-chloro-1-methyl-3H-isothiazolo[4,3-b]pyridine2,2-dioxide (300 mg, 1.37 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (123.47 mg, 0.12mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (103.43 mg, 0.18mmol) and cesium carbonate (486.11 mg, 1.49 mmol) in 1,4-dioxane (30 mL)was stirred at 95° C. for 2 hours. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by areversed-phase chromatography (C18 silica gel; 0.5% sodium bicarbonatein water:methanol (5%˜70%) in 30 min) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(150 mg, 0.22 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=685.2.

Step 5: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of [tert-Butyl carbamate (250 mg, 2.13 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (15 mg, 0.01mmol), Brettphos (8.0 mg, 0.01 mmol),tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.07 mmol) and cesium carbonate (95.0 mg, 0.29 mmol) in1,4-dioxane (1 mL) was stirred for 2 hours at 90° C. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with methanol/dichloromethane](5/95) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.065 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=765.9.

Step 6:[6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)isoquinoline-3,8-diamine

A solution of [tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-2,2-dioxo-3H-isothiazolo[4,3-b]pyridin-5-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(300 mg, 0.39 mmol) and 2,2,2-trifluoroacetic acid (0.2 mL, 0.39 mmol)in dichloromethane (1 mL) was stirred at 25° C. for 30 minutes. Thereaction was quenched by ammonia in methanol (7 mol/L). The solvent wasconcentrated under vacuum. The residue was purified by flashchromatography on C18 (acetonitrile-0.1% sodium bicarbonate in water)afford5-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-1-methyl-1,3-dihydroisothiazolo[4,3-b]pyridine2,2-dioxide (17.1 mg, 0.037 mmol) as a yellow solid. LCMS (ESI):[M+H]⁺=466.2. ¹H NMR (300 MHz, DMSO-d₆) δ 9.69 (s, 1H), 9.35 (s, 1H),8.23 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.45-7.28 (m, 2H), 6.77 (d,J=6.2 Hz, 1H), 6.16 (s, 2H), 5.26 (s, 2H), 4.79 (s, 2H), 3.05 (s, 3H),1.94 (d, J=1.4 Hz, 3H).

Example 1636-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4S,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine(Compound 265),6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4R,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3 ,8-diamine(Compound 266),6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4S,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine(Compound 267) and6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4R,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine(Compound 268)

Step 1: 1-(3,5-dibromo-1H-pyrazol-1-yl)hex-5-en-2-ol

To a solution of 3,5-dibromo-1H-pyrazole (1.5 g, 6.7 mmol) inacetonitrile (20 mL) and 2-(but-3-enyl)oxirane (2 g, 20 mmol) was addedpotassium carbonate (2.8 g, 20 mmol). The resulting mixture was stirredfor 2 hour at 80° C. The reaction was quenched with water and thenextracted with ethyl acetate dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum to afford1-(3,5-dibromo-1H-pyrazol-1-yl)hex-5-en-2-ol (1.4 g, 4.3 mmol) as ayellow oil. LCMS (ESI) [M+H]⁺=323.

Step 2:2-bromo-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-7-ol

A mixture of 1-(3,5-dibromo-1H-pyrazol-1-yl)hex-5-en-2-ol (5.2 g, 16.15mmol), palladium acetate (361 mg, 1.62 mmol), triphenylphosphine (846mg, 3.23 mmol), potassium acetate (4.7 g, 48.45 mmol) andtetrabutylammonium bromide (5.2 g, 16.15 mmol) in N,N-dimethylformamide(50 mL) was stirred overnight at 90° C. After filtration, the filtratewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(1/1) to afford2-bromo-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-7-ol(3.6 g, 14.8 mmol) as an off-white solid. LCMS (ESI) [M+H]⁺=243.

Step 3:2-bromo-7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine

A mixture of2-bromo-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-7-ol (1g, 4.12 mmol) and silver oxide in methyl iodide (15 mL) was refluxedovernight. The resulting solution was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withpetroleum ether/ethyl acetate (2/1) to afford2-bromo-7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(1.02 g, 3.98 mmol) as a white solid. LCMS (ESI) [M+H]⁺=257.

Step 4: tert-butyl N-tert-butoxycarbonyl(5-(8-chloro-7-fluoro-3-((7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

To a solution of2-bromo-7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(1.02 g, 3.97 mmol), tert-butyl N-tert-butoxycarbonyl(5-(3-amino-8-chloro-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(2 g, 3.97 mmol), t-BuBrettPhos Pd G3 (683 mg, 0.8 mmol) andt-BuBrettphos (774 mg, 1.6 mmol) in 1,4-dioxane (20 mL) was added cesiumcarbonate (3.9 g, 12 mmol). The resulting mixture was stirred for 2hours at 120° C. After filtration, the filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (9/1) to afford tert-butylN-tert-butoxycarbonyl(5-(8-chloro-7-fluoro-3-((7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(1.5 g, 2.21 mmol) as a deep-brown solid. LCMS (ESI) [M+H]⁺=679.

Step 5: tert-butylN-tert-butoxycarbonyl-N-(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

A mixture of the tert-butyl N-tert-butoxycarbonyl(5-(8-chloro-7-fluoro-3-((7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(1.5 g, 2.2 mmol), tert-Butyl carbamate (7.7 g, 66 mmol),tris(dibenzylideneacetone)dipalladium (455 mg, 0.44 mmol) and Brettphos(236 mg, 0.44 mmol) in 1,4-dioxane (15 mL) was added cesium carbonate(2.9 g, 0.8 mmol). The resulting solution was stirred for 2 hours at 90°C. After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (9/1) to afford tert-butylN-tert-butoxycarbonyl-N-(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(1.10 g, 1.45 mmol) as a deep-brown solid. LCMS (ESI) [M+H]⁺=760.

Step 6: tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((7-methoxy-4-methylene-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(1.1 g, 1.45 mmol), platinum oxide (120 mg) in methanol (15 mL) wasstirred for 16 hours at the room temperature. After filtration, thefiltrate was concentrated under vacuum to afford tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(800 mg, 1.05 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=762.

Step 7:6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4S,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine,6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4R,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine,6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4S,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamineand6-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4R,75)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine

A solution of the tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(800 mg, 1.05 mmol) in dichloromethane (10 mL) and 2,2,2-trifluoroaceticacid (10 mL) was stirred at 25° C. for 2 hours. The solvent wasconcentrated under vacuum. The crude product was purified byreverse-HPLC (C18 silica gel; 0.5% sodium bicarbonate inwater:ACN=20%-50% in 7 min) to afford the mixture (168 mg, 0.36 mmol) asa yellow solid. The mixture was separated by Chiral-HPLC to afford fourisomers. Compound 265: (56.3 mg) yellow solid. Retention time: 6.06 min(CHIRALPAK IE-3. 0.46*10 cm; 3 μm; MtBE(0.3% IPAmine):EtOH=70:30; 1.0ml/min); LCMS (ESI) [M+H]⁺=462.3; ¹HNMR (300 MHz, DMSO-d₆) δ 9.25 (s,1H), 8.91 (s, 1H), 7.98 (s, 1H), 7.66 (d, J=4.6 Hz, 2H), 6.64 (d, J=6.1Hz, 1H), 6.04 (s, 2H), 5.85 (s, 1H), 5.22 (s, 2H), 4.51 (dd, J=15.2, 5.3Hz, 1H), 4.16 (d, J=14.7 Hz, 1H), 3.53 (s, 1H), 3.27 (s, 3H), 2.89-2.72(m, 1H), 2.16-2.03 (m, 1H), 1.93 (s, 3H), 1.87-1.72 (m, 1H), 1.58-1.42(m, 2H), 1.27 (d, J=6.9 Hz, 3H). Compound 266: (48.7 mg) as a yellowsolid. Retention time: 4.46 min (CHIRALPAK IE-3. 0.46*10 cm; 3 μm;MtBE(0.3% IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=462.3.Compound 268: (17.8 mg) as a yellow solid. Retention time: 6.53 min(CHIRALPAK IE-3. 0.46*10 cm; 3 μm; MtBE(0.3% IPAmine):EtOH=70:30; 1.0ml/min); LCMS (ESI) [M+H]⁺=462.3; ¹H NMR (300 MHz, DMSO-d6) δ 9.25 (s,1H), 8.98 (s, 1H), 7.98 (s, 1H), 7.68 (d, J=6.9 Hz, 2H), 6.69 (d, J=6.1Hz, 1H), 6.05 (s, 2H), 5.87 (s, 1H), 5.22 (s, 2H), 4.34 (d, J=14.0 Hz,1H), 4.03 (dd, J=14.0, 9.5 Hz, 1H), 3.33 (s, 3H), 3.16 (s, 1H), 2.86 (s,1H), 2.13 (s, 1H), 1.93 (s, 3H), 1.86-1.56 (m, 2H), 1.41-1.20 (m, 1H),1.27 (t, J=6.8 Hz, 3H).Compound 267: (17.8 mg) as a yellow solid.Retention time: 11.8 min (CHIRALPAK 0.46*10 cm; 3 μm; MtBE(0.3%IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=462.3.

Example 1645-[8-amino-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-1-ethyl-pyrazole-3-carbonitrile(Compound 269)

Step 1: methyl 5-bromo-1-ethyl-pyrazole-3-carboxylate

A mixture of methyl 5-bromo-1H-pyrazole-3-carboxylate (2. 0 g, 9.76mmol), iodoethane (4.5g, 28.85 mmol) and potassium carbonate (3.0 g,21.74 mmol) in tetrahydrofuran (50 mL) was stirred for 1 hour at 80° C.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withpetroleum ether/ethyl acetate (3/1) to afford methyl5-bromo-1-ethyl-pyrazole-3-carboxylate (1.2 g, 5.15 mmol) as lightyellow solid. LCMS (ESI) [M+H]⁺=233.1.

Step 2: 5-bromo-1-ethyl-pyrazole-3-carboxamide

A mixture of methyl 5-bromo-1-ethyl-pyrazole-3-carboxylate (1.2 g, 5.15mmol) in ammonium hydroxide (10 mL, 30%) was stirred for 1 hour at roomtemperature. The reaction solution was concentrated under vacuum toafford 5-bromo-1-ethyl-pyrazole-3-carboxamide (1.1 g, 5.05 mmol) as awhite solid. LCMS (ESI) [M+H]⁺=218.1.

Step 3: 5-bromo-1-ethyl-1H-pyrazole-3-carbonitrile

Trifluoroacetic anhydride (1.27 g, 6.05 mmol) was added dropwise into asolution of 5-bromo-1-ethyl-pyrazole-3-carboxamide (1.1 g, 5.05 mmol)and triethylamine (1.53 g, 15.14 mmol) in dichloromethane (30 mL) at 0°C. The resulting solution was stirred for 1 hour at room temperature.The mixture was concentrated under vacuum. The residue was purified byreverse phase chromatography (acetonitrile 0-60/0.05% sodium bicarbonatein water) to afford 5-bromo-1-ethyl-1H-pyrazole-3-carbonitrile (1 g,5.00 mmol) as a white solid. LCMS (ESI) [M+H]⁺=200.

Step 4: tert-butylN-[6-(5-cyano-2-ethyl-pyrazol-3-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A solution of[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid (80 mg, 0.16 mmol) and potassium bifluoride (40 mg, 0.41 mmol) in2-methyl-2-propanol (0.80 mL) and water (0.20 mL) was stirred at roomtemperature for 5 hours. 5-Bromo-1-ethyl-pyrazole-3-carbonitrile (80 mg,0.40 mmol), potassium phosphate (96 mg, 0.45 mmol) andtetrakis(triphenylphosphine)palladium (40 mg, 0.03 mmol) was added. Theresulting mixture was stirred at 100° C. for 4.5 hours under theirradiation of microwave. The resulting mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (20/1) to afford tert-butylN-[6-(5-cyano-2-ethyl-pyrazol-3-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(45 mg, 0.077 mmol) as yellow solid. LCMS (ESI) [M+H]⁺=588.3.

Step 5:5-[8-amino-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-1-ethyl-pyrazole-3-carbonitrile

A solution of tert-butylN-[6-(5-cyano-2-ethyl-pyrazol-3-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate (40 mg, 0.07 mmol) and2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (4 mL) was stirredfor 1 hours at room temperature. The mixture was concentrated undervacuum. The reaction mixture was adjusted to pH 7 with triethylamine.The crude product was purified by Prep-HPLC with the followingconditions: Column, Atlantis HILIC OBD Column 19*150*5 μm; mobile phase:Water (10 mmol/L sodium bicarbonate) and ACN (40-50% in 7 min);Detector, UV 254 nm.5-[8-amino-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-1-ethyl-pyrazole-3-carbonitrile(13.8 mg, 0.028 mmol) was obtained as yellow solid. LCMS (ESI)[M+H]⁺=488.4; ¹HNMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.19 (s, 1H),7.76 (s, 1H), 7.19 (s, 1H), 6.94 (d, J=5.8 Hz, 1H), 6.30 (s, 2H), 5.96(s, 1H), 4.97 (s, 2H), 4.61-4.57 (m, 1H), 4.16 (q, J=7.3 Hz, 2H),3.79-3.76 (m, 2H), 2.98 (t, J=5.8 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H), 1.12(d, J=6.8 Hz, 6H).

Example 1652-[[8-amino-7-fluoro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(Compound 270)

Step 1: tert-butyl 3-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate

A mixture of tert-butyl6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (1.0 g, 4.48 mmol),8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (1.5 g, 4.65 mmol),potassium carbonate (1.0 g, 7.25 mmol), palladium acetate (122 mg, 0.37mmol), tricyclohexyl phosphine (210 mg, 0.75 mmol) and trimethylaceticacid (115 mg, 1.13 mmol) in N,N-dimethylacetamide (20 mL) was stirredfor 6 hours at 100° C. The resulting mixture was cooled to roomtemperature and then filtered. The filtrate was concentrated undervacuum. The residue was purified by reverse phase chromatography(acetonitrile 0-55/0.05% sodium bicarbonate in water) to affordtert-butyl 3-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (500 mg, 1.20 mmol) asa yellow solid. LCMS (ESI) [M+H]⁺=418.1.

Step 2: tert-butyl3-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate

A mixture of tert-butyl3-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate(350 mg, 0.84 mmol),2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(455 mg, 1.67 mmol), t-BuBrettPhosPdG3 (350 mg, 0.41 mmol),t-BuBrettPhos (420 mg, 0.73 mmol) and cesium carbonate (805 mg, 2.47mmol) in 1,4-dioxane (35 mL) was stirred at 120° C. for 1.5 hours. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butyl3-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate(300 mg, 0.49 mmol) as yellow solid. LCMS (ESI) [M+H]⁺=609.2.

Step 3: tert-butyl3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate

A mixture of tert-butyl3-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate(260 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium (78 mg, 0.08mmol), Brettphos (91 mg, 0.17 mmol), tert-Butyl carbamate (1.56 g, 13.32mmol) and cesium carbonate (416 mg, 1.28 mmol) in 1,4-dioxane (26 mL)was stirred for 16 hours at 90° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by reverse phasechromatography (acetonitrile 0-60/0.05% sodium bicarbonate in water) toafford tert-butyl3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate(150 mg, 0.22 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=690.3.

Step 4:2-[[8-amino-7-fluoro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butyl3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate(145 mg, 0.21 mmol) in dichloromethane (6 mL) was added2,2,2-trifluoroacetic acid (1.5 mL). The resulting solution was stirredfor 1 hour at 25° C. and then concentrated under vacuum. The residue wasadjusted to pH 7 with triethylamine. The crude product was purified byPrep-HPLC: Atlantis HILIC OBD Column 19*150*5 um; Water (10 mmol/Lsodium bicarbonate) and ACN (20-30% in 7 min) to afford2-[[8-amino-7-fluoro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(17.2 mg, 0.035 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=490.3. ¹HNMR(400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 9.06 (s, 1H), 7.67 (s, 1H), 7.07 (d,J=1.5 Hz, 1H), 6.85 (d, J=6.1 Hz, 1H), 6.07 (s, 2H), 5.96 (s, 1H), 4.97(s, 2H), 4.60 (t, J=6.7 Hz, 1H), 3.97-3.85 (m, 4H), 3.79-3.77 (m, 2H),3.04-2.98 (m, 4H), 2.75 (s, 1H), 1.12 (d, J=6.8 Hz, 6H).

Example 1662-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H,8H-pyrazolo[1,5-c][1,3]thiazepine7,7-dioxide (Compound 271)

Step 1: 2-bromo-6,8-dihydropyrazolo[1,5-c][1,3]thiazepine 7,7-dioxide

A mixture of 1-(allylsulfonylmethyl)-3,5-dibromo-pyrazole (2.0 g, 5.81mmol), triethylamine (4.11 g, 40.7 mmol), palladium acetate (0.2 g, 0.87mmol) and tri(2-methylphenyl)phosphine (530.2 mg, 1.74 mmol) inN,N-dimethylformamide (120 mL) was stirred at 140° C. for 1 hour. Thereaction was cooled to room temperature and then concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with petroleum ether/ethyl acetate (6/1) to afford2-bromo-6,8-dihydropyrazolo[1,5-c][1,3]thiazepine 7,7-dioxide (100 mg,0.38 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=263.2.

Step 2: 2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepine7,7-dioxide

A mixture of 2-bromo-6,8-dihydropyrazolo[1,5-c][1,3]thiazepine7,7-dioxide (200.0 mg, 0.76 mmol), platinium oxide (17.26 mg, 0.08 mmol)and acetic acid (9.12 mg, 0.15 mmol) in methanol (30 mL) was stirred at20° C. for 1 hour under hydrogen (2 atm). After filtration, the filtratewas concentrated under reduced pressure. The residue was purified by areversed-phase flash (C18 silica gel; 0.5% sodium bicarbonate inwater:MeOH=95%˜60% in 20 min) to afford2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepine 7,7-dioxide(130 mg, 0.49 mmol) as a white solid. LCMS45 (ESI) [M+H]⁺=265.3.

Step 3: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(140 mg, 0.28 mmol),2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepine 7,7-dioxide(140 mg, 0.53 mmol), t-BuBrettPhos Pd G3 (190.17 mg, 0.22 mmol),t-BuBrettPhos (134.72 mg, 0.28 mmol) and cesium carbonate (453.7 mg,1.39 mmol) in 1,4-dioxane (28 mL) was stirred for 2 hours at 130° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by a reversed-phase flash (C18 silica gel; 0.5%sodium bicarbonate in water : MeOH=95%˜35% in 20 min) to affordtert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(75 mg, 0.11 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=687.3.

Step 4: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 0.15 mmol), tert-butyl carbamate (425.65 mg, 3.64 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (22.59 mg, 0.02mmol), BrettPhos (15.6 mg, 0.03 mmol) and cesium carbonate (237.2 mg,0.73 mmol) in 1,4-dioxane (10 mL) was stirred for 2 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressureto afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 0.13 mmol) as a brown oil. LCMS (ESI) [M+H]⁺=768.4.

Step 5:6-(5-amino-4-methyl-3-pyridyl)-N3-(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)-7-fluoro-isoquinoline-3,8-diamine

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 0.13 mmol) and 2,2,2-trifluoroacetic acid (10.0 mL, 1.3 mmol)in dichloromethane (10 mL) was stirred at 20° C. for 1 hour. Theresulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to 10 with ammonia in methanol (7 mol/L). Thecrude product was purified by Prep-HPLC (C18 silica gel; 0.5% sodiumbicarbonate in water: CH₃CN =95%˜35% in 45 min) to afford6-(5-amino-4-methyl-3-pyridyl)-N3-(7,7-dioxo-4,5,6,8-tetrahydropyrazolo[1,5-c][1,3]thiazepin-2-yl)-7-fluoro-isoquinoline-3,8-diamine(10.3 mg, 0.02 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=468.2; ¹HNMR(300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.26 (s, 2H), 8.00 (s, 1H), 7.80 (s,2H), 6.74-6.72 (m, 1H), 6.13 (s, 2H), 6.04 (s, 1H), 5.73-5.45 (m, 4H),3.50-3.40 (m, 2H), 2.97-2.94 (m, 2H), 2.03-1.98 (m, 5H).

Example 1672-[[8-amino-7-fluoro-6-(5-methyl-2-oxo-1H-pyridin-4-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid (Compound 272)

Step 1: 4-iodo-2-methoxy-5-methyl-pyridine

A solution of 2-fluoro-4-iodo-5-methylpyridine (5.0 g, 21.1 mmol) andsodium methanolate in methanol (50 mL, 30%) in methanol (50 mL) wasstirred at 80° C. for 2.5 hours. The reaction was quenched by water. Theresulting solution was extracted with ethyl acetate, dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(5/1) to afford 4-iodo-2-methoxy-5-methyl-pyridine (3.7 g, 14.86 mmol)as a light yellow solid. LCMS (ESI) [M+H]⁺=250.

Step 2: (2-methoxy-5-methyl-4-pyridyl)boronic acid

A solution of 4-iodo-2-methoxy-5-methyl-pyridine (200 mg, 0.80 mmol),n-Butyllithium (0.8 mL, 2 mmol) in tetrahydrofuran (5 mL) was stirredfor 1 hour at −78° C. Triisopropoxyborane (1 mL, 4.33 mmol) was addedand then stirred at 25° C. for 1 hour. The reaction was quenched withwater. The resulting solution was extracted with ethyl acetate, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford(2-methoxy-5-methyl-4-pyridyl)boronic acid (300 mg, 0.72 mmol) as awhite solid. LCMS (ESI) [M+H]⁺=168.

Step 3: tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(2-methoxy-5-methyl-4-pyridyl)-8-isoquinolyl]carbamate

A mixture of (2-methoxy-5-methyl-4-pyridyl)boronic acid (54.16 mg, 0.32mmol),[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate (100.0 mg, 0.16 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.87 mg,0.02 mmol) and potassium carbonate (49.24 mg, 0.36 mmol) in 1,4-dioxane(10 mL) and water (1 mL) was stirred at 90° C. for 3 hours undernitrogen. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with methanol/dichloromethane (1:9) to afford tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(2-methoxy-5-methyl-4-pyridyl)-8-isoquinolyl]carbamate(59 mg, 0. 10 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=590.

Step 4:2-[[8-amino-7-fluoro-6-(5-methyl-2-oxo-1H-pyridin-4-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid

A mixture of tert-butylN-[7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(2-methoxy-5-methyl-4-pyridyl)-8-isoquinolyl]carbamate(60 mg, 0.10 mmol) and iodotrimethylsilane (122.16 mg, 0.61 mmol) inacetonitrile (60 mL) was stirred at 80° C. for 2 hours. The solvent wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Atlantis HILIC OBD, 19×150 mm 5 um; water (0.1% FA): CH₃CN=13%-24% B in10 min) to afford2-[[8-amino-7-fluoro-6-(5-methyl-2-oxo-1H-pyridin-4-yl)-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid (11.4 mg, 0.022 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=476.2; ¹HNMR (300 MHz, DMSO-d₆) δ 11.89-11.19 (s, 1H), 9.26 (s,1H), 9.10 (s, 1H), 8.38 (s, 1H), 7.73 (s, 1H), 7.31 (s, 1H), 6.73 (d,J=6.0 Hz, 1H), 6.26 (s, 1H), 6.13 (s, 2H), 5.97 (s, 1H), 4.98 (s, 2H),4.66-4.55 (m, 1H), 3.84-3.74 (m, 2H), 3.04-2.94 (s, 2H), 1.84 (s, 3H),1.13 (d, J=6.8 Hz, 6H).

Example 1682-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-6-(2-hydroxy-2-methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 273)

Step 1: methyl2-(3-bromo-5-(2-(2-hydroxy-2-methylpropylamino)ethyl)-1H-pyrazol-1-yl)acetate

A solution of methyl 2-[5-(2-aminoethyl)-3-bromo-pyrazol-1-yl]acetate(400 mg, 1.53 mmol) and isobutyleneoxide (20 mL, 1.53 mmol) in methanol(10 mL) was stirred at 25° C. for 40 hours. The mixture was concentratedunder vacuum. The crude product would be directly used in the next stepwithout purification. LCMS (ESI) [M+I-I]⁺=334.

Step 2:2-bromo-6-(2-hydroxy-2-methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A solution of methyl2-[3-bromo-5-[2-[(2-hydroxy-2-methyl-propyl)amino]ethyl]pyrazol-1-yl]acetate(200 mg, 0.60 mmol) and triethylamine (604.41 mg, 5.98 mmol) in methanol(50 mL) was stirred at 25° C. for 12 hours. Themixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with methanol/dichloromethane (5/95) to afford2-bromo-6-(2-hydroxy-2-methyl-propyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(40 mg, 0.13 mmol) as a white solid. LCMS (ESI) [M+H]⁺=302.

Step 3:2-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-6-(2-hydroxy-2-methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A mixture of2-bromo-6-(2-hydroxy-2-methyl-propyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(252.05 mg, 0.83 mmol),8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (200 mg,0.70 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct(143.89 mg, 0.14 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(160.99 mg, 0.28 mmol) and cesium carbonate (679.83 mg, 2.09 mmol) in1,4-dioxane (20 mL) was stirred for 3 hours at 100° C. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (1/9) to afford2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(2-hydroxy-2-methyl-propyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.29 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=509.

Step 4: tert-butyl7-fluoro-3-(6-(2-hydroxy-2-methylpropyl)-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of tert-Butyl carbamate (1173.85 mg, 10.02 mmol),2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(2-hydroxy-2-methyl-propyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(170 mg, 0.33 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (69.14 mg, 0.07mmol), Brettphos (71.74 mg, 0.13 mmol) and cesium carbonate (435.54 mg,1.34 mmol) in 1,4-dioxane (15 mL) was stirred for 2 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (1/9) to afford tert-butylN-[7-fluoro-3-[[6-(2-hydroxy-2-methyl-propyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(60 mg, 0.10 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=590.

Step 5:2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-6-(2-hydroxy-2-methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[7-fluoro-3-[[6-(2-hydroxy-2-methyl-propyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(60 mg, 0.10 mmol) in 2,2,2-trifluoroacetic acid (6 mL) was stirred at25° C. for 2 hours. The mixturet was concentrated under vacuum. Thecrude product was purified by Prep-HPLC (Atlantis HILIC OBD, 19×150 mm 5um; water (10 mmol/Lsodium bicarbonate): CH₃CN=20%-45% B in 7 min) toafford2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(2-hydroxy-2-methyl-propyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(14.1 mg, 0.029 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=490.2; ¹H NMR(400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.10 (s, 1H), 8.50 (d, J=5.0 Hz, 1H),8.43 (s, 1H), 7.75 (s, 1H), 7.39 (d, J=5.1 Hz, 1H), 6.78 (d, J=6.1 Hz,1H), 6.12 (s, 2H), 5.96 (s, 1H), 5.01 (s, 2H), 4.59 (s, 1H), 4.00-3.93(m, 2H), 3.82 (s, 2H), 3.15-3.07 (s, 2H), 2.22 (s, 3H), 1.06 (s, 6H).

Example 169(R)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Compound 274) and(S)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 275)

Step 1: methyl 4-bromo-7-hydroxy-5H-cyclopenta[c]pyridine-6-carboxylate

To a solution of ethyl 5-bromonicotimate (5 g, 21.7 mmol) intetrahydrofuran (22 mL) was added dropwise lithium diisopropylamide(23.9 mmol, 2.5 M in tetrahydrofuran) over 5 minutes at −78° C. Theresulting dark red solution was stirred for 30 minutes at −78° C. Methylacrylate (4.9 mL, 54.3 mmol) in tetrahydrofuran (22 mL) was added over 5minutes at −78° C. The reaction was stirred an additional 1.5 hours at−78° C. Then aq. 10% acetic acid (43.5 mL, 76.1 mmol) was added (givinga pH of 4-5) and the reaction was allowed to warm to room temperature.The resulting solution was concentrated under vacuum to afford methyl4-bromo-7-hydroxy-5H-cyclopenta[c]pyridine-6-carboxylate (5.38 g, crude)as dark green amporphous solid. LCMS (ESI) [M+H]⁺=270, 272

Step 2: 4-bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

4-bromo-6-(methoxycarbonyl)-5H-cyclopenta[c]pyridine-7-olate(5.38 g,crude) was dissolved in aq. 6M hydrochloric acid (54 mL) and heated atreflux for 1.5 hours. The reaction was cooled in ice/water and thenadjusted to pH 9 with potassium hydroxide (6 mol/L). The resultingsolution was extracted with ether dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (100/1) to afford4-bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (0.69 g, 3.25 mmol) aspink solid. LCMS (ESI) [M+H]⁺=212, 214.

Step 3: 4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol

To a solution of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (0.69 g,3.3 mmol) in ethanol (10 mL) was added sodium borohydride (188 mg, 5mmol) at 0° C. The resulting solution was stirred overnight at roomtemperature. The reaction was quenched with water and then extractedwith dichloromethane, dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum to afford4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (580 mg, 2.72 mmol) asan off-white solid. LCMS (ESI) [M+H]⁺=214, 216.

Step 4:4-bromo-7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridine

To a solution of 4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (424mg, 2 mmol) in N,N-dimethylformamide (10 mL) was added imidazole (408mg, 6.0 mmol) and tert-butylchlorodiphenylsilane (1.1 g, 4.0 mmol). Thereaction mixture was stirred at 25° C. for 2 hours. The reaction mixturewas diluted with ethyl acetate and then washed with brine. The organiclayers were dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum to afford4-bromo-7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(820 mg, 1.81 mmol) as a light yellow oil. LCMS (ESI) [M+H]⁺=452, 454.

Step 5:7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-ylboronicacid

To a pressure tube was added4-bromo-7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(450 mg, 1 mmol), bis(pinacolato)diboron (2.54 g, 10 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1mmol) and potassium acetate (290 mg, 0.3 mmol) in 1,4-dioxane. Thereaction mixture was stirred at 90° C. for 3 hours. The mixturewasconcentrated under vacuum. The residue was purified by reverse-HPLC toafford7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-ylboronicacid (320 mg, 0.77 mmol) as an off-white solid. LCMS (ESI) [M+H]⁺=418.

Step 6: tert-butyl6-(7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-8-ylcarbamate

To a pressure tube was added7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-ylboronicacid (100 mg, 0.24 mmol),8-(tert-butoxycarbonylamino)-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-6-yltrifluoromethanesulfonate(98 mg, 0.16 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg,0.032 mmol) and potassium carbonate (66 mg, 0.48 mmol) in 1,4-dioxane.The reaction mixture was stirred at 90° C. for 3 hours. The reaction wascooled to room temperature and then concentrated under vacuum. Theresidue was purified by reverse-HPLC to afford tert-butyl6-(7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-8-ylcarbamate(108 mg, 0.13 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=840.

Step 7:2-(8-amino-6-(7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-7-fluoroisoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

To a solution of tert-butyl6-(7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-8-ylcarbamate(108 mg, 0.13 mmol) in dichloromethane (5 mL) was added2,2,2-trifluoroacetic acid (2 mL) at 0° C. The reaction was stirred for30 minutes at room temperature. The resulting solution was concentratedunder vacuum to afford2-(8-amino-6-(7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-7-fluoroisoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(45 mg, 0.061 mmol) as a brown oil. The residue was used directly fornext step. LCMS (ESI) [M+H]⁺=740.

Step 8:(R)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-oneand(S)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of2-(8-amino-6-(7-(tert-butyldiphenylsilyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-7-fluoroisoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(45 mg, 0.061 mmol) in dichloromethane (10 mL) and tetrabutylammoniumfluoride (0.1 mL) was stirred at 25° C. for 2 hours. The mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(C18 silica gel; 0.5% sodium bicarbonate in water:ACN=20%-50% in 30mins) to afford the racemic product (25 mg, 0.049 mmol) as a whitesolid. The racemic product was separated by Chiral-HPLC to afford twoisomers: Compound 275: (7.1 mg, 0.014 mmol) as a white solid. Retentiontime: 2.68 min (CHIRALPAK IE-3. 0.46*10 cm; 3 μm; MtBE(0.3%IPAmine):EtOH=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=502.2; ¹H NMR (300MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.09 (s, 1H), 8.58 (s, 1H), 8.45 (s, 1H),7.72 (s, 1H), 6.85 (d, J=6.2 Hz, 1H), 6.12 (s, 2H), 5.97 (s, 1H), 5.52(d, J=5.8 Hz, 1H), 5.26 (dd, J=12.6, 6.4 Hz, 1H), 4.97 (s, 2H),4.64-4.54 (m, 1H), 3.78 (s, 2H), 3.03-2.71 (m, 4H), 2.40-2.31 (m, 1H),1.88-1.78 (m, 1H), 1.12 (d, J=6.8 Hz, 6H). Compound 274: (7.8 mg, 0.015mmol) as a white solid. Retention time: 3.73 min (CHIRALPAK IE-3.0.46*10 cm; 3 μm; MtBE(0.3% IPAmine):EtOH=70:30; 1.0 ml/min).

Example 1702-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-methyl-4,5-dihydro-7H-pyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide (Compound 276)

Step 1: methyl 5-bromo-2-(methylsulfamoylmethyl)pyrazole-3-carboxylate

A mixture of methyl 3-bromo-1H-pyrazole-5-carboxylate (100 mg, 0.49mmol), 1-bromo-N-methyl-methanesulfonamide (91.72 mg, 0.49 mmol) andpotassium carbonate (134.63 mg, 0.98 mmol) in 1-methyl-2-pyrrolidinone(10 mL) was stirred at 50° C. for 1 hour. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with petroleum ether/ethylacetate (3/1) to afford methyl5-bromo-2-(methylsulfamoylmethyl)pyrazole-3-carboxylate (100 mg, 0.32mmol) as a white solid. LCMS (ESI) [M+H]⁺=312.

Step 2:1-[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]-N-methyl-methanesulfonamide

To a solution of methyl5-bromo-2-(methylsulfamoylmethyl)pyrazole-3-carboxylate (60 mg, 0.19mmol) in dichloromethane (10 mL) was added diisobutylaluminium hydride(0.19 mL, 0.38 mmol) at 0° C. The resulting solution was stirred for 1hour at 0° C. The reaction was quenched with methanol. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (acetonitrile 0-50/0.1%ammonium hydroxide in water) to afford1-[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]-N-methyl-methanesulfonamide(35 mg, 0.12 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=284.

Step 3: 2-bromo-5-methyl-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide

A mixture of1-[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]-N-methyl-methanesulfonamide(200 mg, 0.70 mmol) and triphenylphosphine (370.25 mg, 1.41 mmol) intetrahydrofuran (10 mL) was stirred at 25° C. for 5 minutes. Thendiisopropyl azodicarboxylate (284.38 mg, 1.41 mmol) was added. Thereaction was stirred at 25° C. for 2 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (5/1) to afford2-bromo-5-methyl-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide (170 mg, 0.64 mmol) as a white solid. LCMS (ESI) [M+H]⁺=266.

Step 4: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(321.3 mg, 0.64 mmol),2-bromo-5-methyl-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide (170 mg, 0.64 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (132.23 mg, 0.13mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (147.69 mg, 0.26mmol) and cesium carbonate (624.76 mg, 1.92 mmol) in 1,4-dioxane (20 mL)was stirred for 6 hours at 100° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(3/2) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(110 mg, 0.16 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=688.

Step 5: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 0.15 mmol), tert-butyl carbamate (340.47 mg, 2.91 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (30.08 mg, 0.03mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.6 mg, 0.06mmol) and cesium carbonate (142.12 mg, 0.44 mmol) in 1,4-dioxane (15 mL)was stirred for 6 hours at 100° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(2/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(105 mg, 0.14 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=769.

Step 6: 6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)isoquinoline-3,8-diamine

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 0.13 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (3 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum. The reaction mixture was adjusted to pH 9with ammonia in methanol (7 mol/L). The resulting residue was purifiedby reverse phase chromatography (acetonitrile 0-40/0.1% sodiumbicarbonate in water) to afford6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(5-methyl-6,6-dioxo-4,7-dihydropyrazolo[5,1-d][1,2,5]thiadiazin-2-yl)isoquinoline-3,8-diamine(55.3 mg, 0.12 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=469; ¹HNMR(400 MHz, DMSO-d₆) δ 9.33 (s, 1H), 9.28 (s, 1H), 7.98 (s, 1H), 7.70 (s,1H), 7.66 (s, 1H), 6.65-6.64 (d, J=4.0 Hz, 1H), 6.16 (s, 1H), 6.09 (s,2H), 5.57 (s, 2H), 5.22 (s, 2H), 4.59 (s, 2H), 2.86 (s, 3H), 1.92 (s,3H).

Example 1712-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(oxetan-3-ylmethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 277)

Step 1:2-bromo-6-(oxetan-3-ylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (200 mg,0.87 mmol) in N,N-dimethylformamide (5 mL) was added NaH (79.98 mg, 3.48mmol) at 0° C. and then stirred for 5 minutes. 3-(iodomethyl)oxetane(344.26 mg, 1.74 mmol) was added and then stirred at 25° C. for 1 hour.The reaction was quenched by water. The resulting solution was extractedwith ethyl acetate, dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (96/4) to afford2-bromo-6-(oxetan-3-ylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(192 mg, 0.64 mmol) as a orange solid. LCMS (ESI) [M+H]⁺=300.3.

Step 2: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[6-(oxetan-3-ylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(214.5 mg, 0.43 mmol),2-bromo-6-(oxetan-3-ylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(192.01 mg, 0.64 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (88.28 mg, 0.09mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (98.6 mg, 0.17mmol) and cesium carbonate (347.57 mg, 1.07 mmol) in 1,4-dioxane (19 mL)was stirred at 100° C. for 4 hours. The mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (96/4) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[6-(oxetan-3-ylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(231.3 mg, 0.32 mmol) as orange solid. LCMS15 (ESI) [M+H]⁺=722.3.

Step 3: Tert-butylN-[7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[6-(oxetan-3-ylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(231.3 mg, 0.32 mmol), tert-butyl carbamate (936.78 mg, 8.01 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (66.3 mg, 0.06mmol) and Brettphos (68.67 mg, 0.13 mmol) in 1,4-dioxane (20 mL) wasadded cesium carbonate (261.02 mg, 0.80 mmol) at 25° C. The reactionsolution was stirred at 90° C. for 1 hour. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with petroleum ether/ethylacetate (1/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[6-(oxetan-3-ylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(105.4 mg, 0.1313 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=803.3.

Step 4:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(oxetan-3-ylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[6-(oxetan-3-ylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(66 mg, 0.08 mmol) in oxydibenzene (2.0 mL) was stirred for 3 hours at180° C. The reaction was dissolved in N,N-dimethylformamide and thenpurified by Prep-HPLC (Atlantis HILIC OBD Column 19*150 mm*5 um; Water(10 mmol/L sodium bicarbonate)/ ACN=15%-30% in 7 min) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(oxetan-3-ylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(4.6 mg, 0.0092 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=503.3. ¹HNMR(300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.06 (s, 1H), 7.98 (s, 1H), 7.69-7.66(m, 2H), 6.72-6.70 (m, 1H), 6.06 (s, 2H), 5.97 (s, 1H), 5.22 (s, 2H),4.97 (s, 2H), 4.63-4.59 (m, 2H), 4.34-4.30 (m, 2H), 3.83 (m, 2H),3.71-3.69 (m, 2H), 3.25-3.21 (m, 1H), 2.99-2.98 (m, 2H), 1.92 (s, 3H).

Example 1722-((8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 278)

Step 1:2-methoxy-4-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 5-bromo-2-methoxy-4-methyl-3-nitro-pyridine (2.0 g, 8.1mmol), bis(pinacolato)diboron (10.28 g, 40.48 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.19 g,1.62 mmol) and potassium acetate (2.38 g, 24.29 mmol) in 1,4-dioxane (40mL) was stirred at 100° C. for 2 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (1/1) to afford2-methoxy-4-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(2.1 g, 7.14 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=295.

Step 2:8-chloro-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)isoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (1.0 g, 3.1mmol),2-methoxy-4-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.37 g, 4.65 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (226.97 mg,0.31 mmol) and potassium carbonate (941.37 mg, 6.82 mmol) in 1,4-dioxane(30 mL) and water (3 mL) was stirred at 90° C. for 2 hours. The solventwas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(1/1) to afford8-chloro-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)isoquinolin-3-amine(780 mg, 2.15 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=363.

Step 3:2-bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (500 mg,2.17 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride(156.48 mg, 60% purity, 6.52 mmol) at 0° C. The resulting mixture wasstirred for 30 minutes at 0° C. Then 2-iodo-1,1-difluoroethane (2.09 g,10.87 mmol) was added. The mixture was stirred at 25° C. for 3 hours.The reaction was quenched with water. The resulting solution wasextracted with ethyl acetate, dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by reverse phase chromatography (acetonitrile 0-40/0.1% sodiumbicarbonate in water) to afford2-bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(480 mg, 1.63 mmol) as a white solid. LCMS (ESI) [M+H]⁺=294.

Step 4: 2-[[8-chloro-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)-3soquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of8-chloro-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)isoquinolin-3-amine(300 mg, 0.83 mmol),2-bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(291.88 mg, 0.99 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct (171.2 mg, 0.17 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (191.21 mg, 0.33 mmol)and cesium carbonate (674.04 mg, 2.07 mmol) in 1,4-dioxane (45 mL) wasstirred at 100° C. for 7 hours. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(4/1) to afford2-[[8-chloro-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(175 mg, 0.30 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=576.

Step 5: tert-butylN-[3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(84 mg, 0.15 mmol), tert-butyl carbamate (427.16 mg, 3.65 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (30.19 mg, 0.03mmol), Brettphos (31.27 mg, 0.06 mmol) and cesium carbonate (237.74 mg,0.73 mmol) in 1,4-dioxane (8 mL) was stirred at 90° C. for 2 hours. Themixturewas concentrated under vacuum. The resulting residue was purifiedby reverse phase chromatography (acetonitrile 0-50/0.1% sodiumbicarbonate in water) to afford tert-butylN-[3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)-8-isoquinolyl]carbamate(40 mg, 0.061 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=657.

Step 6: tert-butyl (6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-3-86-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-7-fluoroisoquinolin-8-yl)carbamate

A mixture of tert-butylN-[3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-(6-methoxy-4-methyl-5-nitro-3-pyridyl)-8-isoquinolyl]carbamate(40 mg, 0.06 mmol) and raney nickel (60 mg, 0.06 mmol) in methanol (7mL) was stirred at 25° C. for 1 hour under hydrogen (1 atm). Afterfiltration, the filtrate was concentrated under vacuum to affordtert-butyl(6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-3-((6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)-7-fluoroisoquinolin-8-yl)carbamate(30 mg, 0.048 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=627.

Step 7:2-[[8-amino-6-(5-amino-6-methoxy-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[6-(5-amino-6-methoxy-4-methyl-3-pyridyl)-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-8-isoquinolyl]carbamate(20 mg, 0.03 mmol) and 2,2,2-trifluoroacetic acid (3 mL) indichloromethane (3 mL) was stirred at 25° C. for 1 hour. The reactionwas concentrated under vacuum. The residue was adjusted to pH 10 withammonia in methanol (7 mol/L). The crude product was purified byPrep-HPLC (XBridge Shield RP18 OBD Column 30*150 mm, 5 um; Water (10mmol/L sodium bicarbonate): ACN (30% to 45%) in 7 min) to afford2-[[8-amino-6-(5-amino-6-methoxy-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(1.8 mg, 0.0034 mmol) as a dark yellow solid. LCMS (ESI) [M+H]⁺=527.2;¹HNMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.06 (s, 1H), 7.70 (s, 1H),7.34 (s, 1H), 6.70 (d, J=6.1 Hz, 1H), 6.29-5.89 (m, 4H), 5.05 (s, 2H),4.80 (s, 2H), 3.93 (m, 6H), 3.80 (s, 1H), 3.06 (m, 2H), 1.95 (d, J=1.6Hz, 3H).

Example 173(1R,2R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 279),(1S,2S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 280),(1R,2S,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 281),(1S,2R,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 282),(1S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 120) and(1R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 121)

Step 1: Diphenyl(propyl)sulfonium tetrafluoroborate

To a solution of silver tetrafluoroborate (2 g, 10.31 mmol) indichloromethane (20 mL) was added 1-iodopropane (1.75 g, 10.31 mmol) anddiphenyl sulfide (5.76 g, 30.93 mmol) at 0° C. The reaction was stirredat 35° C. for 15 hours. The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was washed withdichloromethane-ether to afford diphenyl(propyl)sulfoniumtetrafluoroborate (2 g, 6.32 mmol) as a white solid. LCMS (ESI)[M+H]⁺=229.

Step 2: trans-tert-butyl2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

To a solution of diphenyl(propyl)sulfonium tetrafluoroborate (1.50 g,4.75 mmol) in 1,2-dimethoxyethane (30 mL) and dichloromethane (3 mL) wasadded lithium diisopropylamide (5.54 ml, 11.09 mmol) at −78° C. Theresulting mixture was stirred for 1 hour at −78° C. Then tert-butyl(Z)-3-(1-methylpyrazol-4-yl)prop-2-enoate (330 mg, 1.58 mmol) was addedand stirred at −78° C. to 25° C. for 15 hours. The reaction was quenchedwith water. The resulting mixture was extracted with dichloromethane anddried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford trans-tert-butyl2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate as a mixture of4 stereoisomers where pyrazole is trans to ester (350 mg, 1.40 mmol) asa brown oil. LCMS (ESI) [M+H]⁺=251.

Step 3: trans-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylicacid

A solution of trans-tert-butyl2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (350 mg, 1.4mmol) and 2,2,2-trifluoroacetic acid (8 mL) in dichloromethane (3 mL)was stirred at 25° C. for 1 hour. The mixture was concentrated undervacuum. The resulting residue was purified by reverse phasechromatography (acetonitrile 0-40/0.1% HCl in water) to affordtrans-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid (260mg, 1.34 mmol) as a brown oil. LCMS (ESI) [M+H]⁺=195.

Step 4: trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A solution of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(675 mg, 1.34 mmol),trans-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid(338.86 mg, 1.74 mmol) and pyridine (3 mL) in dichloromethane (15 mL)was added phosphorus oxychloride (410.66 mg, 2.68 mmol) at 0° C. Thereaction was stirred at 25° C. for 30 minutes and then quenched bywater. The resulting mixture was extracted with dichloromethane, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(900 mg, 1.32 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=679.

Step 5: trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(1.3 g, 1.91mmol), tert-butyl carbamate (5.61 g, 47.85 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (396.21 mg, 0.38mmol), Brettphos (410.38 mg, 0.77 mmol) and cesium carbonate (3.12 g,9.57 mmol) in 1,4-dioxane (80 mL) was stirred at 90° C. for 2 hours. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5) to afford trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(1 g, 1.32 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=760.

Step 6:(1R,2R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1S,2S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1R,2S,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1S,2R,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamideand(1R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

A solution of trans-tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(1.0 g, 1.32 mmol) and 2,2,2-trifluoroacetic acid (10 mL) indichloromethane (10 mL) was stirred at 25° C. for 1 hour. The reactionwas concentrated under vacuum. The residue was purified by Prep-HPLCwith the following conditions (XBridge Prep OBD C18 Column 30×150 mm 5um; Water (10 mmol/L sodium bicarbonate): ACN (22% to 40%) in 7 min) toafford the mixture of the six isomeric products (230 mg, 0.50 mmol). Themixture was purified by chiral-HPLC to afford six isomers. Cyclopropanestereochemistry for ethylcyclopropane-containing isomers (Compounds279-282) (Pyrazole trans to amide; Ethyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarilyassigned): Compound 279: (47.7 mg, 0.104 mmol) as a yellow solid.Retention time: 6.036 min (CHIRALPAK ID-3, 0.46*10 cm; 3 μm;

-   MtBE(0.1% DEA):EtOH=70:30; 2 ml/min). LCMS (ESI) [M+H]⁺=460.2; ¹HNMR    (300 MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.41 (s, 1H), 8.29 (s, 1H), 7.99    (s, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.29 (s, 1H), 6.86 (d, J=6.1    Hz, 1H), 6.24 (s, 2H), 5.25 (s, 2H), 3.80 (s, 3H), 2.37-2.27 (m,    1H), 2.18 (m, 1H), 1.92 (d, J=1.5 Hz, 3H), 1.62-1.45 (m, 1H), 1.22    (m, 2H), 0.89 (m, 3H). Compound 280: (56 mg, 0.12 mmol) as a yellow    solid. Retention time: 7.559 min (CHIRALPAK ID-3, 0.46*10 cm; 3 μm;    MtBE(0.1% DEA):EtOH=70:30; 2 ml/min). LCMS (ESI) [M+H]⁺=460.2; ¹HNMR    (300 MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.41 (s, 1H), 8.29 (s, 1H), 7.99    (s, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.29 (s, 1H), 6.86 (d, J=6.1    Hz, 1H), 6.24 (s, 2H), 5.25 (s, 2H), 3.80 (s, 3H), 2.38-2.15 (m,    2H), 1.92 (d, J=1.5 Hz, 3H), 1.62-1.43 (m, 1H), 1.23 (m, 2H), 0.89    (m, 3H). Compound 281: (13.5 mg, 0.029 mmol) as a yellow solid.    Retention time: 4.98 min (CHIRALPAK ID-3, 0.46*10 cm; 3 μm;    MtBE(0.1% DEA):EtOH=70:30; 2 ml/min). LCMS (ESI) [M+H]⁺=460.2; ¹HNMR    (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.40 (s, 1H), 8.31 (s, 1H), 7.99    (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.25 (d, J=0.8 Hz, 1H), 6.87    (d, J=6.1 Hz, 1H), 6.24 (s, 2H), 5.25 (s, 2H), 3.77 (s, 3H),    2.29-2.17 (m, 2H), 1.92 (d, J=1.5 Hz, 3H), 1.83-1.42 (m, 3H), 0.92    (t, J=7.3 Hz, 3H). Compound 282: (10.2 mg, 0.022 mmol) as a yellow    solid. Retention time: 3.847 min (CHIRALPAK ID-3, 0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):EtOH=70:30; 2 ml/min). LCMS (ESI) [M+H]⁺=460.2; ¹HNMR    (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.40 (s, 1H), 8.31 (s, 1H), 7.99    (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.25 (d, J=0.8 Hz, 1H), 6.87    (d, J=6.1 Hz, 1H), 6.24 (s, 2H), 5.25 (s, 2H), 3.77 (s, 3H),    2.29-2.17 (m, 2H), 1.92 (d, J=1.5 Hz, 3H), 1.83-1.42 (m, 3H), 0.92    (t, J=7.3 Hz, 3H). Compound 120:    N-[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]-2,2-dimethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxamide    (16.6 mg, 0.036 mmol) as a yellow solid. Retention time: 6.312 min    (CHIRALPAK ID-3, 0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):EtOH=70:30; 2 ml/min). LCMS (ESI) [M+H]⁺=460.2; ¹HNMR    (300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 9.41 (s, 1H), 8.32 (s, 1H), 7.99    (s, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 7.25 (s, 1H), 6.87 (d, J=6.2    Hz, 1H), 6.23 (s, 2H), 5.25 (s, 2H), 3.79 (s, 3H), 2.33-2.19 (m,    2H), 1.92 (d, J=1.4 Hz, 3H), 1.29 (s, 3H), 0.99 (s, 3H). Compound    121:    N-[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]-2,2-dimethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxamide    (16 mg, 0.035 mmol) as a yellow solid. Retention time: 5.166 min    (CHIRALPAK ID-3, 0.46*10 cm; 3 μm; MtBE(0.1% DEA):EtOH=70:30; 2    ml/min). LCMS (ESI) [M+H]⁺=460.2; ¹NMR (300 MHz, DMSO-d₆) δ 10.63    (s, 1H), 9.41 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H),    7.51 (s, 1H), 7.26 (s, 1H), 6.87 (d, J=6.1 Hz, 1H), 6.24 (s, 2H),    5.25 (s, 2H), 3.79 (s, 3H), 2.38-2.15 (m, 2H), 1.92 (d, J=1.5 Hz,    3H), 1.28 (s, 3H), 0.99 (s, 3H).

Example 1742-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-cyclopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(Compound 283)

Step 1:[2-bromo-6-cyclopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of cyclopropylboronic acid (448.06 mg, 5.22 mmol),2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (400.0 mg,1.74 mmol), copper(II)acetate (567.97 mg, 1.74 mmol), triethylamine(526.82 mg, 5.22 mmol) and pyridine (206.03 mg, 2.61 mmol) intetrahydrofuran (5 mL) was stirred for 12 h at 60° C. under oxygen. Thereaction mixture was diluted with water (50 mL). The resulting mixturewas extracted with dichloromethane, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with methanol/dichloromethane(2/98) to afford[2-bromo-6-cyclopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(260mg, 0.96 mmol) as a yellow oil. LC/MS (ESI) [M+H]⁺=270.1

Step 2: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6-cyclopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-6-cyclopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.56 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(195 mg, 0.39 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (80.25 mg, 0.08mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (175.5 mg, 0.30mmol) and cesium carbonate (379.88 mg, 1.17 mmol) in 1,4-dioxane (10 mL)was stirred for 3 hours at 100° C. under nitrogen. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (1/10) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6-cyclopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(160 mg, 0.23 mmol) as a brown oil. LCMS (ESI) [M+H]⁺=692.2.

Step 3: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6-cyclopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butyl carbamate (812.8 mg, 6.94 mmol), tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6-cyclopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(160.0 mg, 0.23 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (48.0 mg, 0.05mmol), Brettphos (25.6 mg, 0.05 mmol) and cesium carbonate (304 mg, 0.93mmol) in 1,4-dioxane (2 mL) was stirred for 3 hours at 90° C. undernitrogen. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with methanol/dichloromethane (1/10) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6-cyclopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(160.0 mg, 0.21 mmol) as a brown oil. LCMS (ESI) [M+H]⁺=772.9

Step 4:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-cyclopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6-cyclopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(160 mg, 0.21 mmol) and 2,2,2-trifluoroacetic acid (2 mL, 0.21 mmol) indichloromethane (2 mL) was stirred at 25° C. for 3 hours. The reactionmixture was adjusted to pH 7 with ammonia in methanol (7 mol/L). Themixture was concentrated under vacuum. The residue was purified by flashchromatography by flash chromatography on C18 to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-cyclopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(11.4 mg, 0.02 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=472.5; ¹HNMR(300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.08 (s, 1H), 8.00 (s, 1H), 7.71 (d,J=3.4 Hz, 2H), 6.73 (d, J=6.1 Hz, 1H), 6.08 (s, 2H), 5.97 (s, 1H), 5.30(s, 2H), 4.95 (s, 2H), 3.87-3.77 (m, 2H), 3.06-2.96 (m, 2H), 2.81-2.70(m, 1H), 1.95 (s, 3H), 0.75-0.60 (m, 2H), 0.71-0.59 (m, 2H).

Example 1752-[[8-amino-6-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(Compound 284)

Step 1: 8-bromo-4H-pyrido[4,3-b][1,4]oxazin-3-one

A mixture of 3-amino-5-bromo-4-pyridinol (5 g, 26.45 mmol), chloroacetylchloride (3.25 g, 28.78 mmol), potassium carbonate (11.0 g, 79.71 mmol)in N,N-dimethylformamide (30 mL) was stirred at 100° C. for 12 hours.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluted withdichloromethane/methanol (10/1) to afford8-bromo-4H-pyrido[4,3-b][1,4]oxazin-3-one (3.5 g, 15.28 mmol) as a lightyellow solid. LCMS (ESI) [M+H]⁺=229.

Step 2: 8-bromo-3,4-dihydro-2H-pyrido(4,3-b)(1,4) oxazine

A mixture of 8-bromo-4H-pyrido(4,3-b)(1,4)oxazin-3-one (1.0 g, 4.37mmol) in tetrahydrofuran (15 mL) was added borane-tetrahydrofurancomplex (13.1 mL, 13.1 mmol) at 0° C. The reaction was stirred for 12hours at 60° C. The resulting mixture was added dropwise to a solutionof methanol (5 mL) and hydrochloric acid (5 mL, 12 mol/L) at 60° C. for5 hours. The reaction mixture was diluted with water (50 mL). Theresulting mixture was extracted with ethyl acetate, dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum to afford 8-bromo-3,4-dihydro-2H-pyrido(4,3-b)(1,4) oxazine (1 g,4.7 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=215.0.

Step 3: tert-butyl8-bromo-2,3-dihydropyrido(4,3-b)(1,4)oxazine-4-carboxylate

A mixture of di-tert-butyldicarbonate (1.67 g, 7.67 mmol),8-bromo-3,4-dihydro-2H-pyrido(4,3-b)(1,4)oxazine (1.1 g, 5.12 mmol),triethylamine (1.5 g, 15.3 mmol), in dichloromethane (30 mL) was stirredat 25° C. for 3 hours. After filtration, the filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluted with dichloromethane/methanol (10/1) to afford tert-butyl8-bromo-2,3-dihydropyrido(4,3-b)(1,4)oxazine-4-carboxylate (770 mg, 2.44mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=315.2.

Step 4: tert-butyl8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[4,3-b][1,4]oxazine-4-carboxylate

A mixture of tert-butyl8-bromo-2,3-dihydropyrido(4,3-b)(1,4)oxazine-4-carboxylate (350 mg, 1.11mmol), bis(pinacolato)diboron (2.8 g, 11.15 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (161.0 mg,0.22 mmol) and potassium acetate (327.8 mg, 3.34 mmol) in 1,4-dioxane (5mL) was stirred at 90° C. for 3 hours. After filtration, the filtratewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluted with dichloromethane/methanol (30/1)to afford tert-butyl8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[4,3-b][1,4]oxazine-4-carboxylate(240 mg, 0.66 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=362.2.

Step 5: tert-butyl8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido(4,3-b)(1,4)oxazine-4-carboxylate

A mixture of(4-tert-butoxycarbonyl-2,3-dihydropyrido[4,3-b][1,4]oxazin-8-yl)boronicacid (100.0 mg, 0.36 mmol),[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate (111.1 mg, 0.18 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.33 mg,0.02 mmol) and potassium carbonate (75.56 mg, 0.55 mmol) in 1,4-dioxane(2 mL) was stirred under nitrogen at 90° C. for 2 hours. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (1/10) to afford [tert-butyl8-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-2,3-dihydropyrido[4,3-b][1,4]oxazine-4-carboxylate(120 mg, 0.17 mmol) as a brown oil.

Step 6:2-[[8-amino-6-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butyl8-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-2,3-dihydropyrido[4,3-b][1,4]oxazine-4-carboxylate(140 mg, 0.20 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (2 mL) was stirred at 25° C. for 3 hours. The reactionmixture was adjusted to pH 7 with ammonia in methanol (7 mol/L). Themixture was concentrated under vacuum. The residue was purified byprep-HPLC to afford2-[[8-amino-6-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(10.3 mg, 0.02 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=502.5. ¹H NMR(300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.08 (s, 1H), 7.93 (s, 1H), 7.78 (s,1H), 7.71 (s, 1H), 6.82 (d, J=5.9 Hz, 1H), 6.30 (s, 1H), 6.03 (s, 1H),5.97 (s, 1H), 4.98 (s, 2H), 4.70-4.55 (m, 1H), 4.28-4.21 (m, 2H),3.83-3.74 (m, 2H), 3.40 (s, 2H), 3.04-2.95 (m, 2H), 1.13 (d, J=6.8 Hz,6H).

Example 1762-[[8-amino-6-(5-amino-4-ethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(Compound 286)

Step 1: 3-bromo-4-iodo-5-nitro-pyridine

A mixture of 3-bromo-4-chloro-5-nitropyridine (5.0 g, 21.06 mmol) andpotassium iodide (70 g, 422.02 mmol) in acetonitrile (300 mL) wasstirred for 16 hours at 80° C. The resulting solution was cooled to roomtemperature and then filtrated. The filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with petroleum ether/ethyl acetate (10/1) to afford3-bromo-4-iodo-5-nitro-pyridine (6.5 g, 19.76 mmol) as a red solid. LCMS(ESI) [M+H]⁺=328.7.

Step 2: 3-bromo-5-nitro-4-vinyl-pyridine

A mixture of 3-bromo-4-iodo-5-nitro-pyridine (5.0 g, 15.2 mmol),potassium trifluoro(vinyl)borate (2.6 g, 19.41 mmol), sodium carbonate(4.8 g, 45.28 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.1 g, 1.5mmol) in 1,4-dioxane (300 mL) and water (30 mL) was stirred for 3 daysat 50° C. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith petroleum ether/ethyl acetate (10/1) to afford3-bromo-5-nitro-4-vinyl-pyridine (2.8 g, 12.22 mmol). LCMS (ESI)[M+H]=229.

Step 3: 5-bromo-4-ethyl-pyridin-3-amine

A mixture of 3-bromo-5-nitro-4-vinyl-pyridine (500 mg, 2.18 mmol),platinum dioxide (100 mg, 0.44 mmol) and acetic acid (5 drops) inmethanol (20 mL) was stirred for 4 hour at 20° C. under hydrogen. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (2/1) to afford 5-bromo-4-ethyl-pyridin-3-amine (220mg, 1.09 mmol) as light yellow oil. LCMS (ESI) [M+H]⁺=201.

Step 4: tert-butylN-(5-bromo-4-ethyl-3-pyridyl)-N-tert-butoxycarbonyl-carbamate

A solution of 5-bromo-4-ethyl-pyridin-3-amine (200 mg, 0.99 mmol) anddi-tert-butyldicarbonate (650 g, 2.98 mmol) in tetrahydrofuran (2 mL)was stirred at 90° C. for 2 hours in a seal tube. The organic layer wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(10/1) to afford tert-butylN-(5-bromo-4-ethyl-3-pyridyl)-N-tert-butoxycarbonyl-carbamate (180 mg,0.45 mmol). LCMS (ESI) [M+H]⁺=401.

Step 5: [5-[bis(tert-butoxycarbonyl)amino]-4-ethyl-3-pyridyl]boronicacid

A mixture of tert-butylN-(5-bromo-4-ethyl-3-pyridyl)-N-tert-butoxycarbonyl-carbamate (200 mg,0.50 mmol), bis(pinacolato)diboron (600 mg, 2.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.10mmol), potassium acetate (150 mg, 1.53 mmol) in N,N-dimethylacetamide (5mL) was stirred for 2 hours at 90° C. The resulting mixture was cooledto room temperature and then filtered. The filtrate was concentratedunder vacuum. The residue was purified by reverse phase chromatography(acetonitrile 0-70/0.05% sodium bicarbonate in water) to afford[5-[bis(tert-butoxycarbonyl)amino]-4-ethyl-3-pyridyl]boronic acid (100mg, 0.27 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=367.3.

Step 6:tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-ethylpyridin-3-yl)carbamate

A mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(13 mg, 0.02 mmol), potassium carbonate (65 mg, 0.47 mmol),[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate(100 mg, 0.16 mmol),[5-[bis(tert-butoxycarbonyl)amino]-4-ethyl-3-pyridyl]boronic acid (90mg, 0.25 mmol) in 1,4-dioxane (5 mL) and water (0.05 mL) was stirred for3 hours at 90° C. The resulting mixture was cooled to room temperatureand then filtered. The filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/ methanol (40/1) to affordtert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-ethylpyridin-3-yl)carbamate(46 mg, 0.058 mmol) as a red solid. LCMS (ESI) [M+H]⁺=789.4.

Step 7:2-[[8-amino-6-(5-amino-4-ethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-ethyl-3-pyridyl]carbamate(41 mg, 0.05 mmol) in dichloromethane (5 mL) and 2,2,2-trifluoroaceticacid (1 mL) was stirred for 1 hour at room temperature. The mixture wasconcentrated under vacuum. The residue was dissolved inN,N-dimethylformamide and the solution was adjusted pH 7withtriethylamine. The resulting solution was purified by Prep-HPLC with(XBridge prep C18 OBD Column 19*150 mm 5 um; water (10 mmol/L sodiumbicarbonate)/CH₃CN=25%-45% in 7 min) to afford2-[[8-amino-6-(5-amino-4-ethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(8.1 mg, 0.017 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=489.3.¹HNMR(400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.06 (s, 1H), 7.98 (s, 1H), 7.70 (s,1H), 7.59 (s, 1H), 6.70 (d, J=5.9 Hz, 1H), 6.06 (s, 2H), 5.97 (s, 1H),5.25 (s, 2H), 4.96 (s, 2H), 4.63-4.55 (m, 1H), 3.77 (s, 2H), 2.98 (s,2H), 2.35-2.33(m, 2H), 1.12 (d, J=6.7 Hz, 6H), 0.92 (t, J=7.4 Hz, 3H).

Example 1772-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-ethyl-4H,6H-pyrazolo[1,5-c]thiazole5,5-dioxide (Compound 287)

Step 1: 3-(bromomethylsulfanyl)prop-1-ene

To a solution of polyformaldehyde (16 g, 0.13 mol) in toluene (110 mL)was added 270 mL of hydrogen bromide (aq, 48%) over 5 minutes. Themixture was stirred for 20 minutes at 20° C. The reaction was thenwarmed to 40° C. and allyl mercaptan (45 g, 606.96 mmol) was added viaaddition funnel over 20 minutes. The mixture was then heated to 50° C.and then stirred for an additional 2 hours. The reaction was quenched bywater. The resulting solution was extracted with ethyl acetate, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford 3-(bromomethylsulfanyl)prop-1-ene(20 g, crude) as a light yellow oil. GCMS (ESI) M=168.0.

Step 2: 1-(allylsulfanylmethyl)-3,5-dibromo-pyrazole

To a solution of 3,5-dibromo-1H-pyrazole (10 g, 44.27 mmol) inN,N-dimethylformamide (100 mL) was added potassium carbonate (12.22 g,88.55 mmol), tetrabutylammonium iodide (0.82 g, 2.21 mmol) and3-(bromomethylsulfanyl)prop-1-ene (22.19 g, 132.82 mmol). The reactionwas stirred at 20° C. for 3 hours. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(8/1) to afford 1-(allylsulfanylmethyl)-3,5-dibromo-pyrazole (10 g,32.05 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=310.9.

Step 3: 1-(allylsulfonylmethyl)-3,5-dibromo-pyrazole

To a solution of 1-(allylsulfanylmethyl)-3,5-dibromo-pyrazole (10 g,32.05 mmol) in dichloromethane (400 mL) was added 3-chloroperoxybenzoicacid (12.13 g, 70.51 mmol) at 0° C. The resulting solution was stirredat 0° C. for 3 hours. The reaction was quenched by sodium thiosulfateand sodium carbonate aqueous solution. The resulting solution wasextracted with dichloromethane, dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withpetroleum ether/ethyl acetate (4/1) to afford1-(allylsulfonylmethyl)-3,5-dibromo-pyrazole (1.5 g, 4.36 mmol) as awhite solid. LCMS (ESI) [M+H]⁺=345.1.

Step 4: 2-bromo-4-methyl-7H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide

A mixture of triethylamine (1.47 g, 14.53 mmol),tris(2-methylphenyl)phosphine (264.48 mg, 0.87 mmol), palladium acetate(97.66 mg, 0.44 mmol) and 1-(allylsulfonylmethyl)-3,5-dibromo-pyrazole(1 g, 2.91 mmol) in N,N-dimethylformamide (50 mL) was stirred at 90° C.for 1 hour. The mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (9/1) to afford2-bromo-4-methyl-7H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide (500 mg,1.90 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=263.2.

Step 5: 2-bromo-4-methyl-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine6,6-dioxide

A mixture of 2-bromo-4-methyl-7H-pyrazolo[1,5-c][1,3]thiazine6,6-dioxide (500 mg, 1.9 mmol) and sodium borohydride (252.75 mg, 6.65mmol) in methanol (30 mL) was stirred at 20° C. for 1 hour. The reactionwas quenched by water. The resulting mixture was extracted with ethylacetate, dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The residue was purified by areversed-phase flash (C18 silica gel; 0.5% sodium bicarbonate in water:CH₃CN=70%˜5% in 30 min) to afford2-bromo-4-methyl-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide(280 mg, 1.06 mmol) as a colorless solid. LCMS (ESI) [M+H]⁺=267.3.

Step 6: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(150 mg, 0.30 mmol),2-bromo-4-methyl-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide(237.21 mg, 0.89 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (123.47 mg, 0.12mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (103.43 mg, 0.18mmol) and cesium carbonate (291.67 mg, 0.89 mmol) in 1,4-dioxane (15 mL)was stirred for 2 hours at 120° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by areversed-phase flash (C18 silica gel; 0.5% sodium bicarbonate in water:CH₃CN=70%˜5% in 30 min) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.07 mmol) as a yellow solid. LCMS45 (ESI) [M+H]⁺=687.3.

Step 7: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.07 mmol), tert-butyl carbamate (213.1 mg, 1.82 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (26.36 mg, 0.03mmol), BrettPhos (19.5 mg, 0.04 mmol) and cesium carbonate (118.6 mg,0.36 mmol) in 1,4-dioxane (8 mL) was stirred at 90° C. for 2 hours.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (1/10) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.07 mmol) as a brown oil. LCMS (ESI) [M+H]⁺=768.4.

Step 8:6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)isoquinoline-3,8-diamineformate salt

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.07 mmol) and 2,2,2-trifluoroacetic acid (12 mL) indichloromethane (3 mL) was stirred at 20° C. for 1 hour. The resultingsolution was concentrated under vacuum. The crude product was purifieddirectly by Prep-HPLC (XBridge Prep C18 OBD Column19*15 mm 5 umC-0013;0.1% HCOOH in water: CH₃CN=93%˜60% in 7 min) afford6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-N3-(4-methyl-6,6-dioxo-5,7-dihydro-4H-pyrazolo[1,5-c][1,3]thiazin-2-yl)isoquinoline-3,8-diamine(1.3 mg, 0.003 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=468.2; ¹HNMR(400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 9.30 (s, 1H), 8.39 (s, 1H), 7.98 (s,1H), 7.68-7.66 (m, 2H), 6.69-6.67 (m, 1H), 6.25 (s, 1H), 6.11 (s, 2H),5.46-5.38 (m, 2H), 5.22 (s, 2H), 4.67-4.63 (m, 1H), 2.03-1.99 (m, 2H),1.92 (s, 3H), 1.14-1.10 (m, 3H).

Example 1782-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(cyclopropylmethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one formate salt (Compound 288)

Step 1:2-bromo-6-(cyclopropylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (200 mg,0.87 mmol) and sodium hydride (79.98 mg, 3.48 mmol) inN,N-dimethylformamide (5 mL) was stirred at 20° C. for 5 minutes. Then(iodomethyl)cyclopropane (316.44 mg, 1.74 mmol) was added. The mixturewas stirred at 20° C. for 1 hour. The reaction was quenched with water.The resulting solution was extracted with ethyl acetate, dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(98/2) to afford2-bromo-6-(cyclopropylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(191 mg, 0.67 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=284.1.

Step 2: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[6-(cyclopropylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

To a mixture of2-bromo-6-(cyclopropylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(180.5 mg, 0.64 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(213 mg, 0.42 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (87.66 mg, 0.08mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (97.91 mg,0.17 mmol) in 1,4-dioxane (18 mL) was added cesium carbonate (345.14 mg,1.06 mmol) at 25° C. The resulting solution was stirred at 100° C. for12 hours. The mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (96/4) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[6-(cyclopropylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(225 mg, 0.32 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=706.4

Step 3: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[6-(cyclopropylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

To a mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[6-(cyclopropylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(225 mg, 0.32 mmol), tert-butyl carbamate (933.11 mg, 7.97 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (65.95 mg, 0.06mmol) and Brettphos (68.31 mg, 0.13 mmol) in 1,4-dioxane (10 mL) wasadded cesium carbonate (259.66 mg, 0.80 mmol) at rt. The resultingsolution was stirred at 90° C. for 1 hour. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (95/5) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[6-(cyclopropylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(67 mg, 0.085 mmol) as orange oil. LCMS (ESI) [M+H]⁺=787.2.

Step 4:2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(cyclopropylmethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one;formic acid

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[6-(cyclopropylmethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(65 mg, 0.08 mmol) and 2,2,2-trifluoroacetic acid (1.0 mL, 0.08 mmol) indichloromethane (3.0 mL) was stirred at 20° C. for 1 hour. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH 8with ammonia in methanol (7 mol/L). The crude product was purified byPrep-HPLC (XBridge Prep C18 OBD Column 19×150 mm 5 um; Water (0.1% FA)and ACN (5%-18%) in 10 min) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(cyclopropylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid (13.5 mg, 0.025 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=487.3; ¹HNMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.07 (s, 1H),8.24 (s, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 6.72-6.70 (m,1H), 6.06 (s, 2H), 5.98(s, 1H), 5.22 (s, 2H), 4.99 (s, 2H), 3.93-3.89(m, 2H), 3.28-3.26 (m, 2H), 3.09-3.05 (m, 2H), 1.93 (s, 3H), 1.01 (s,1H), 0.48-0.44 (m, 2H), 0.29 (m, 2H).

Example 1792-((8-amino-7-fluoro-6-(5-hydroxy-4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one;formic acid (Compound 289)

Step 1: 3-bromo-5-(methoxymethoxy)-4-methyl-pyridine

A mixture of 5-bromo-4-methyl-pyridin-3-ol (213 mg, 1.13 mmol) andsodium hydride (52.11 mg, 2.27 mmol, 60% purity) in tetrahydrofuran (5mL) was stirred at 0° C. for 30 minutes. Bromomethyl methyl ether(169.87 mg, 1.36 mmol) was added. The mixture was stirred at 0° C. for 1hour. The reaction was quenced with methanol. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(4/1) to afford 3-bromo-5-(methoxymethoxy)-4-methyl-pyridine (190 mg,0.82 mmol) as a white solid. LCMS (ESI) [M+H]⁺=232

Step 2: [5-(methoxymethoxy)-4-methyl-3-pyridyl]boronic acid

A mixture of 3-bromo-5-(methoxymethoxy)-4-methyl-pyridine (714 mg, 3.08mmol), bis(pinacolato)diboron (781 mg, 3.08 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (450 mg,0.62 mmol) and potassium acetate (904 mg, 9.23 mmol) in 1,4-dioxane (15mL) was stirred at 90° C. for 2 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (95/5) to afford[5-(methoxymethoxy)-4-methyl-3-pyridyl]boronic acid (300 mg, 1.52 mmol)as a brown solid. LCMS (ESI) [M+H]⁺=198.

Step 3:8-chloro-7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]isoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (300 mg, 0.93mmol), [5-(methoxymethoxy)-4-methyl-3-pyridyl]boronic acid (275 mg, 1.4mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (68mg, 0.09 mmol) and potassium carbonate (385 mg, 2.79 mmol) in1,4-dioxane (10 mL) and water (1 mL) was stirred at 90° C. for 1 hour.The mixture was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford8-chloro-7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]isoquinolin-3-amine(145 mg, 0.42 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=348.

Step 4:2-[[8-chloro-7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of8-chloro-7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]isoquinolin-3-amine(135 mg, 0.39 mmol),2-bromo-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (142mg, 0.58 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct(80 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (89mg, 0.16 mmol) and cesium carbonate (381 mg, 1.16 mmol) in 1,4-dioxane(5 mL) was stirred at 100° C. for 12 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (10/1) to afford2-[[8-chloro-7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.098 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=511.

Step 5: tert-butylN-[7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(50 mg, 0.10 mmol), tert-butyl carbamate (286 mg, 2.45 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (20 mg, 0.020mmol), Brettphos (15.74 mg, 0.03 mmol) and cesium carbonate (95 mg, 0.29mmol) in 1,4-dioxane (3 mL) was stirred at 90° C. for 2 hours. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-[7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(40 mg, 0.067 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=592.

Step 6:2-[[8-amino-7-fluoro-6-(5-hydroxy-4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid

A mixture of tert-butylN-[7-fluoro-6-[5-(methoxymethoxy)-4-methyl-3-pyridyl]-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(30 mg, 0.05 mmol) and hydrochloric acid (0.17 mL, 0.5 mmol) indichloromethane (2 mL) was stirred at 20° C. for 1 hour. The mixture wasconcentrated under vacuum. The reaction mixture was adjusted to pH 8with ammonia in methanol (7 mol/L). The crude product was purified byPrep-HPLC (XBridge Prep C18 OBD Column 19×150 nm 5 um; water (0.1% FA):CH₃CN=5%-19% in 7 min) to afford2-[[8-amino-7-fluoro-6-(5-hydroxy-4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid (1.4 mg, 0.0028 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=448. ¹HNMR (400 MHz, CD₃OD) δ 9.16(s, 1H), 8.07 (s, 1H), 7.94 (s,1H), 7.64 (s, 1H), 6.86 (d, J=6.0 Hz, 1H), 6.07 (s, 1H), 5.06 (s, 2H),3.92(t, J=6.0 Hz, 2H), 3.16(t, J=6.0 Hz, 2H), 3.10 (s, 3H), 2.15 (s,3H).

Example 1802-(8-amino-7-fluoro-6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)isoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 290)

Step 1: 3-bromo-5-((tert-butyldimethylsilyloxy)methyl)-4-methylpyridine

A solution of (5-bromo-4-methyl-3-pyridyl)methanol (500 mg, 2.47 mmol)and imidazole (505.42 mg, 7.42 mmol) in N,N-dimethylformamide (15 mL)was stirred at 25° C. for 10 minutes. TBSCl (742.39 mg, 4.95 mmol) wasadded and stirred at 25° C. for 2 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (16/84) to afford(5-bromo-4-methyl-3-pyridyl)methoxy-tert-butyl-dimethyl-silane (820 mg,2.07 mmol) as a white oil. LC/MS (ESI) [M+H]⁺=316.

Step 2:5-((tert-butyldimethylsilyloxy)methyl)-4-methylpyridin-3-ylboronic acid

A mixture of(5-bromo-4-methyl-3-pyridyl)methoxy-tert-butyl-dimethyl-silane (1.65 g,5.22 mmol), bis(pinacolato)diboron (1.99 g, 7.82 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (381.84 mg,0.52 mmol) and potassium acetate (1.28 g, 13.04 mmol) in 1,4-dioxane (18mL) was stirred for 12 hours at 90° C. After filtration, the filtratewas concentrated under reduced pressure. The resulting residue waspurified by reverse phase chromatography (acetonitrile 0-40/0.1% sodiumbicarbonate in water) to afford[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]boronicacid (480 mg, 1.70 mmol) as a white solid. LC/MS (ESI) [M+H]⁺=282.

Step 3:6-(5-((tert-butyldimethylsilyloxy)methyl)-4-methylpyridin-3-yl)-8-chloro-7-fluoroisoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (382 mg, 1.18mmol),[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]boronicacid (499.66 mg, 1.78 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (86.7 mg,0.12 mmol), potassium carbonate (359.6 mg, 2.61 mmol) in 1,4-dioxane (15mL) and water (1.5 mL) was stirred for 3 hours at 90° C. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (7:3) to afford6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]-8-chloro-7-fluoro-isoquinolin-3-amine(320 mg, 0.74 mmol) as a yellow solid. LC/MS (ESI) [M+H]⁺=432.

Step 4:2-(6-(5-((tert-butyldimethylsilyloxy)methyl)-4-methylpyridin-3-yl)-8-chloro-7-fluoroisoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A mixture of2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(181.42 mg, 0.67 mmol),6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]-8-chloro-7-fluoro-isoquinolin-3-amine(240.0 mg, 0.56 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (115.0 mg, 0.11mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (128.66 mg, 0.22mmol) and cesium carbonate (543.32 mg, 1.67 mmol) in 1,4-dioxane (20 mL)was stirred for 12 hours at 100° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(10/1) to afford2-[[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (56 mg, 0.090 mmol) as ayellow solid. LCMS (ESI) [M+H]⁺=623.

Step 5: tert-butyl 6-(5-((tert-butyldimethylsilyloxy)methyl)-4-methylpyridin-3-yl)-7-fluoro-3-(6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)isoquinolin-8-ylcarbamate

A mixture of2-[[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (60.0 mg, 0.10 mmol), tert-butyl carbamate (337.91mg, 2.89 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct(19.93 mg, 0.020 mmol), Brettphos (20.68 mg, 0.040 mmol) and cesiumcarbonate (125.54 mg, 0.39 mmol) in 1,4-dioxane (5 mL) was stirred for12 hours at 90° C. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with methanol/dichloromethane (12:88) to affordtert-butylN-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(60 mg, 0.085 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=704.

Step 6:2-(8-amino-7-fluoro-6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)isoquinolin-3-ylamino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[6-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-3-pyridyl]-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(50.0 mg, 0.070 mmol) in 2,2,2-trifluoroacetic acid (5 mL) was stirredat 25° C. for 12 hours. The mixture was concentrated under vacuum. Thecrude product was purified by Prep-HPLC (Atlantis HILIC OBD, 19×150mmSum; water (10 mmol/L sodium bicarbonate): CH₃CN=20%-40% B in 7 min) toafford2-[[8-amino-7-fluoro-6-[5-(hydroxymethyl)-4-methyl-3-pyridyl]-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(5.1 mg, 0.010 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=490.2; ¹H NMR(300 MHz, Methanol-d₄) δ 9.17 (s, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 7.66(s, 1H), 6.87 (d, J=6.2 Hz, 1H), 6.07 (s, 1H), 5.06 (s, 2H), 4.80 (s,2H), 4.75 (d, J=6.7 Hz, 1H), 3.88 (t, J=6.0 Hz, 2H), 3.14 (d, J=6.1 Hz,2H), 2.32 (d, J=1.3 Hz, 3H), 1.25 (d, J=6.8 Hz, 6H).

Example 1812-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2-methoxyethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 291)

Step 1:2-bromo-6-(cyclopropylmethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a mixture of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (200 mg,0.86 mmol) in N,N-dimethylformamide (6 mL) was added sodium hydride(79.18 mg, 3.48 mmol) at 0° C. The mixture was stirred for 20 mins at20° C. 1-Iodo-2-methoxy-ethane (485.06 mg, 2.6 mmol) was added. Themixture was then stirred at 20° C. for 1 hour. The reaction was quenchedwith water. The resulting mixture was extracted with ethyl acetate,dried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5) to afford2-bromo-6-(2-methoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(172 mg, 0.31 mmol) as orange oil. LCMS (ESI) [M+H]⁺=288.1.

Step 2: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[6-(2-methoxyethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(199 mg, 0.82 mmol),2-bromo-6-(2-methoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(172 mg, 1.24 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (82.12 mg, 0.08mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (92.32 mg, 0.16mmol) and cesium carbonate (389.23 mg, 1.22 mmol) in 1,4-dioxane (16 mL)was stirred at 95° C. for 2 hours. The mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (96/4) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[6-(2-methoxyethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(222 mg, 0.17 mmol) as a canary yellow solid. LCMS (ESI) [M+H]⁺=710.3.

Step 3: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[6-(2-methoxyethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

To a mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[6-(2-methoxyethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(222 mg, 0.31 mmol), tert-butyl carbamate (915.51 mg, 7.81 mmol),Tris(dibenzylideneacetone)dipalladium-chloroform adduct (64.71 mg, 0.06mmol) and Brettphos (67.02 mg, 0.13 mmol) in 1,4-dioxane (10 mL) wasadded cesium carbonate (254.76 mg, 0.78 mmol) at 25° C. The resultingsolution was stirred at 90° C. for 1 hour. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (94/6) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[6-(2-methoxyethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(131 mg, 0.17 mmol) as orange solid. LCMS (ESI) [M+H]⁺=791.4.

Step 4:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2-methoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[6-(2-methoxyethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(131 mg, 0.17 mmol) and 2,2,2-trifluoroacetic acid (1.0 mL) indichloromethane (2 mL) was stirred at 20° C. for 1 hour. The mixture wasconcentrated under vacuum. The reaction mixture was adjusted to pH 8with a solution of amine in methanol. The crude product was purified byPrep-HPLC (XBridge Prep C18 OBD Column 19×150 mm 5 um C-0013; Water(0.1% FA) and ACN (5%-15%) in 7 min)to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2-methoxyethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(34.2 mg, 0.064 mol) as light yellow solid. LCMS (ESI) [M+H]⁺=491.2;¹HNMR (300 MHz, DMSO) δ 9.25 (s, 1H), 9.06 (s, 1H), 7.98 (s, 1H), 7.70(s, 1H), 7.66 (s, 1H), 6.72-6.70 (m, 1H), 6.06 (s, 2H), 5.97 (s, 1H),5.22 (s, 2H), 4.98 (s, 2H), 3.87-3.85 (m, 2H), 3.57-3.54 (m, 2H),3.46-3.43 (m, 2H), 3.26 (s, 3H), 3.03-3.01 (m, 2H), 1.93 (s, 3H).

Example 1822-((8-amino-7-fluoro-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 292)

Step 1: tert-butyl3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

A mixture of[7-fluoro-8-(isopropoxycarbonylamino)-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid (100 mg, 0.21 mmol), tert-butyl3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (120 mg,0.40 mmol), potassium phosphate (40 mg, 0.19 mmol), sodium acetate (50mg, 0.61 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.05mmol) in acetonitrile (10 mL) and water (1 mL) was stirred at 90° C. for1 hour. After filtration, the filtrate was concentrated under vacuum.The residue was purified by Prep-TLC with ethyl acetate/methanol (50/1)to afford tert-butyl3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate(43 mg, 0.065 mmol) as yellow solid. LCMS (ESI) [M+H]⁺=662.

Step 2:2-[[8-amino-7-fluoro-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of tert-butyl3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate(40 mg, 0.06 mmol), 2,2,2-trifluoroaceticacid (1 mL) and dichloromethane(5mL) was stirred for 1 hour at room temperature. The mixture wasconcentrated under vacuum. The residue was dissolved in dichloromethaneand then adjusted to pH 7 with ammonia in methanol (7 mol/L). Themixture was concentrated under vacuum. The residue was purified byPrep-HPLC (XBridge prep C18 OBD, 19*150 mm, 5um; Water (0.05% NH₃H₂O):ACN (7-24% in 7 min)) to afford2-[[8-amino-7-fluoro-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(4 mg, 0.0087 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=462.¹HNMR (300MHz, DMSO-d₆) δ 9.17 (s, 1H), 9.01 (s, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.63(s, 1H), 6.74 (d, J=6.3 Hz, 1H), 5.98 (s, 3H), 4.99 (s, 2H), 4.06-4.05(m, 4H), 3.83-3.82 (m, 2H), 3.18-3.17 (m, 2H), 3.05-3.03 (m, 2H), 2.96(s, 3H), 2.69 (s, 1H).

Example 1832-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H,8H-pyrazolo[5,1-e][1,2,6]thiadiazepine7,7-dioxide (Compound 293)

Step 1: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(6-methyl-4-methylene-7,7-dioxo-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-6-methyl-4-methylene-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepine7,7-dioxide (200 mg, 0.68 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(309.89 mg, 0.62 mmol), t-BuBrettphos (165.67 mg, 0.34 mmol),t-BuBrettphos Pd G3 (233.85 mg, 0.27 mmol) and cesium carbonate (557.93mg, 1.71 mmol) in 1,4-dioxane (15 mL) was stirred for 1 hour at 120° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (4/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(6-methyl-4-methylene-7,7-dioxo-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 0.14 mmol) as a brown solid . LCMS (ESI) [M+H]⁺=714

Step 2: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-4-methylene-7,7-dioxo-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butyl carbamate (262.44 mg, 2.24 mmol), tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(6-methyl-4-methylene-7,7-dioxo-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(80 mg, 0.11 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (23.19 mg, 0.02mmol), Brettphos (18.05 mg, 0.03 mmol) and cesium carbonate (91.29 mg,0.28 mmol) in 1,4-dioxane (10 mL) was stirred for 2 hours at 100° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (2/98) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-4-methylene-7,7-dioxo-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(60 mg, 0.076 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=795

Step 3: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(4,6-dimethyl-7,7-dioxo-5,8-dihydro-4H-pyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-4-methylene-7,7-dioxo-5,8-dihydropyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.06 mmol) and Raney nickel (10 mg) in methanol (10 mL) wasstirred at 25° C. for 12 hours. After filtration, the filtrate wasconcentrated under reduced pressure to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(4,6-dimethyl-7,7-dioxo-5,8-dihydro-4H-pyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(45 mg, 0.05 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=797

Step 4:6-(5-amino-4-methyl-3-pyridyl)-N3-(4,6-dimethyl-7,7-dioxo-5,8-dihydro-4H-pyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)-7-fluoro-isoquinoline-3,8-diamine;formic acid

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(4,6-dimethyl-7,7-dioxo-5,8-dihydro-4H-pyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.06 mmol) and 2,2,2-trifluoroacetic acid (1 mL) indichloromethane (2 mL) was stirred at 25° C. for 2 hours. The mixturewas concentrated under vacuum. The residue was adjusted to pH 10 withammonia in methanol (7 mol/L). The resulting residue was purified byreverse phase chromatography (acetonitrile 0-40/0.1% FA in water) toafford6-(5-amino-4-methyl-3-pyridyl)-N3-(4,6-dimethyl-7,7-dioxo-5,8-dihydro-4H-pyrazolo[5,1-e][1,2,6]thiadiazepin-2-yl)-7-fluoro-isoquinoline-3,8-diamine;formic acid (2.9 mg, 0.0053 mmol) as a brown solid. LCMS (ESI)[M+H]⁺=497. ¹HNMR (400 MHz, CD₃OD) δ 9.16 (s, 1H), 8.39 (s, 1H),7.78-7.77 (d, J=4.0 Hz, 2H), 6.90-6.88 (d, J=8.0 Hz, 1H), 6.11 (s, 1H),5.92-5.88 (d, J=16 Hz, 1H), 5.36-5.32 (d, J=16 Hz, 1H), 3.79-3.55 (m,3H), 3.13 (s, 3H), 2.09 (s, 3H), 1.39-1.38 (d, J=4.0 Hz, 3H)

Example 184[2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-ethyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(Compound 298)

Step 1:2-bromo-6-ethyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (1 g, 4.0mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (313 mg,13.0 mmol) at 0° C. The mixture was stirred for 30 minutes at 0° C.Iodoethane (1.3 g, 9.0 mmol) was added to this reaction solution at 0°C. and then stirred for 4 hours. The reaction was quenched by water. Theresulting solution was extracted with ethyl acetate, dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by reverse phasechromatography (acetonitrile-0.1% sodium bicarbonate in water) to afford2-bromo-6-ethyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (1 g,3.89 mmol) as a white solid. LCMS (ESI) [M+H]⁺=258.1.

Step 2: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6-ethyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-6-ethyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (140.0mg, 0.54 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(272.8 mg, 0.54 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (112.27 mg, 0.11mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (125.4 mg, 0.22mmol) and cesium carbonate (530.45 mg, 1.63 mmol) in 1,4-dioxane (2 mL)was stirred at 100° C. for 4 hours. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/ petroleum ether(1/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6-ethyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(70 mg, 0.10 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=680.2.

Step 3: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6-ethyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[(6-ethyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(40.0 mg, 0.06 mmol), tert-butyl carbamate (206.76 mg, 1.76 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (12.0 mg, 0.01mmol), Brettphos (6.32 mg, 0.01 mmol) and cesium carbonate (76.8 mg,0.24 mmol) in 1,4-dioxane (2 mL) was stirred for 4 hours at 90° C. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with methanol/dichloromethane (1/4)to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6-ethyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(40 mg, 0.053 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=706.9.

Step 4:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-ethyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[(6-ethyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(40.0 mg, 0.05 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (2 mL) was stirred at 25° C. for 2 hours. The mixturewas concentrated under vacuum. The residue was purified by flashchromatography on C18 (acetonitrile-0.1% sodium bicarbonate in water)afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-ethyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(2.4 mg, 0.01 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=460.5. ¹HNMR(300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.07 (s, 1H), 7.99 (s, 1H), 7.69 (d,J=9.4 Hz, 2H), 6.72 (d, J=6.1 Hz, 1H), 6.07 (s, 2H), 5.99 (s, 1H), 5.24(s, 2H), 4.97 (s, 2H), 3.90-3.84 (m, 2H), 3.50-3.43 (m, 2H), 3.05-2.90(m, 2H), 1.94 (s, 3H), 1.09-1.01 (m, 3H).

Example 1852-((8-amino-6-(5-amino-4,6-dimethylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 299)

Step 1: dimethyl 2-(5-bromo-4-methyl-3-nitro-2-pyridyl)propanedioate

To a solution of dimethyl malonate (3.15 g, 23.86 mmol) in1-methyl-2-pyrrolidinone (100 mL) was added sodium hydride (0.95 g,23.86 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for 10mins. 5-Bromo-2-chloro-4-methyl-3-nitropyridine (4.0 g, 15.91 mmol) wasadded. The mixture was stirred at 40° C. for 12 hours. The reaction wasquenched with water. The reaction mixture was diluted with water. Theresulting mixture was extracted with ethyl acetate, dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum to afford dimethyl2-(5-bromo-4-methyl-3-nitro-2-pyridyl)propanedioate (3.5 g, 10.08 mmol)as a brown solid. LCMS (ESI) [M+H]⁺=347.

Step 2: 5-bromo-2,4-dimethyl-3-nitro-pyridine

A solution of dimethyl2-(5-bromo-4-methyl-3-nitro-2-pyridyl)propanedioate (3.5 g, 10.08 mmol)in hydrochloric acid (20 mL, 12 mol/L) was stirred at 100° C. for 12hours. The mixture was concentrated under vacuum. The reaction mixturewas adjusted to pH 10 with sodium hydroxide solution (10%). Theresulting solution was extracted with ethyl acetate, dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/9) to afford 5-bromo-2,4-dimethyl-3-nitro-pyridine (1.5 g, 6.49 mmol)as a yellow solid. LCMS (ESI) [M+H]^(+b =231.)

Step 3: (4,6-dimethyl-5-nitropyridin-3-yl)boronic acid

A mixture of 5-bromo-2,4-dimethyl-3-nitro-pyridine (1.5 g, 6.49 mmol),bis(pinacolato)diboron (3.29 g, 12.98 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (950.44 mg,1.30 mmol) and potassium acetate (1.91 g, 19.48 mmol) in 1,4-dioxane (30mL) was stirred for 12 hours at 90° C. After filtration, the filtratewas concentrated under reduced pressure. The reaction mixture wasadjusted to pH 10 with sodium hydroxide solution (10%). The water layerwas washed with diethyl ether. The solution was adjusted to pH 5 withhydrochloric acid (1 mol/L). The resulting mixture was extracted withethyl acetate, dried with anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum to afford(4,6-dimethyl-5-nitropyridin-3-yl)boronic acid (1.1 g, 3.95 mmol) as abrown solid. LCMS (ESI) [M+H]⁺=197.

Step 4:8-chloro-6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-isoquinolin-3-amine

A mixture of (4,6-dimethyl-5-nitro-3-pyridyl)boronic acid (364.58 mg,1.86 mmol), 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (400 mg, 1.24mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(90.79 mg, 0.12 mmol) and potassium carbonate (342.31 mg, 2.48 mmol) in1,4-dioxane (15 mL) was stirred for 12 hours at 90° C. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford8-chloro-6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-isoquinolin-3-amine(220 mg, 0.63 mmol) as a yellow solid. LCMS (ESI) [M+H]+=347.

Step 5:2-[[8-chloro-6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of8-chloro-6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-isoquinolin-3-amine(220 mg, 0.63 mmol),2-bromo-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(154.87 mg, 0.63 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (65.67 mg, 0.06mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (108.37 mg, 0.13mmol) and cesium carbonate (620.52 mg, 1.9 mmol) in 1,4-dioxane (15 mL)was stirred for 12 hours at 100° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford2-[[8-chloro-6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(210 mg, 0.41 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=510

Step 6: tert-butylN-[6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(260 mg, 0.51 mmol), tert-butyl carbamate (1194.66 mg, 10.2 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (105.55 mg, 0.10mmol), Brettphos (82.14 mg, 0.15 mmol) and cesium carbonate (415.56 mg,1.27 mmol) in 1,4-dioxane (20 mL) was stirred at 90° C. for 2 hours.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol (10/1) to afford tert-butylN-[6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(150 mg, 0.25 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=591

Step 7: tert-butylN-[6-(5-amino-4,6-dimethyl-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of tert-butylN-[6-(4,6-dimethyl-5-nitro-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(150 mg, 0.25 mmol) and Raney nickel (50 mg) in methanol (10 mL) wasstirred for 5 hours at 25° C. under H₂. After filtration, the filtratewas concentrated under reduced pressure to afford tert-butylN-[6-(5-amino-4,6-dimethyl-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(100 mg, 0.17 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=561

Step 8:2-[[8-amino-6-(5-amino-4,6-dimethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of tert-butylN-[6-(5-amino-4,6-dimethyl-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(100 mg, 0.18 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (2 mL) was stirred at 25° C. for 2 hours. The mixturewas concentrated under vacuum. The reaction mixture was adjusted to pH10 with ammonia in methanol (7 mol/L). The resulting residue waspurified by reverse phase chromatography (acetonitrile 0-40/0.1% ammoniain water) to afford2-[[8-amino-6-(5-amino-4,6-dimethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(22.2 mg, 0.04 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=561. ¹HNMR(300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 9.04 (s, 1H), 7.67 (s, 1H), 7.59 (s,1H), 6.69 (d, J=6.0 Hz, 1H), 6.03 (s, 2H), 5.97 (s, 1H), 4.96 (s, 2H),4.90 (s, 2H), 3.89-3.80 (m, 2H), 3.03-3.00 (m, 2H), 2.94 (s, 3H), 2.35(s, 3H), 1.95 (s, 3H).

Example 1862-(8-amino-6-(2-amino-3-methylpyridin-4-yl)-7-fluoroisoquinolin-3-ylamino)-6-(2,2-difluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 300)

Step 1: 4-bromo-N,N-bis(4-methoxybenzyl)-3-methylpyridin-2-amine

A solution of 4-bromo-3-methyl-pyridin-2-amine (500.0 mg, 2.67 mmol),sodium hydride (427.72 mg, 10.69 mmol) in N,N-dimethylformamide (50 mL)was stirred for 30 minutes at 0° C. 4-methoxybenzyl chloride (2.09 g,13.37 mmol) was added and stirred at 25° C. for 2 hours. The reactionwas quenched with water. The reaction mixture was diluted with ethylacetate. The resulting mixture was washed with water and the organiclayers were combined. The organic layer was dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (2/8) to afford4-bromo-N,N-bis[(4-methoxyphenyl)methyl]-3-methyl-pyridin-2-amine (1.1g, 2.57 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=427.

Step 2: 2-(bis(4-methoxybenzyl)amino)-3-methylpyridin-4-ylboronic acid

A mixture of4-bromo-N,N-bis[(4-methoxyphenyl)methyl]-3-methyl-pyridin-2-amine (1.1g, 2.57 mmol), bis(pinacolato)diboron (980.51 mg, 3.86 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (188.43 mg,0.26 mmol) in 1,4-dioxane (15 mL) was stirred for 3 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressure.The resulting residue was purified by reverse phase chromatography(acetonitrile 5-85/0.1% sodium bicarbonate in water) to afford2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]boronic acid(750 mg, 1.91 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=393.

Step 3:6-(2-(bis(4-methoxybenzyl)amino)-3-methylpyridin-4-yl)-8-chloro-7-fluoroisoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (400 mg, 1.24mmol), 2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]boronicacid (729.76 mg, 1.86 mmol), potassium carbonate (376.55 mg, 2.73 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (90.79 mg,0.12 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred for 2hours at 90° C. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with ethyl acetate/petroleum ether (1/1) to afford6-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]-8-chloro-7-fluoro-isoquinolin-3-amine(480 mg, 0.88 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=543.

Step 4:2-(6-(2-(bis(4-methoxybenzyl)amino)-3-methylpyridin-4-yl)-8-chloro-7-fluoroisoquinolin-3-ylamino)-6-(2,2-difluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A mixture of2-bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(100.19 mg, 0.34 mmol),6-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]-8-chloro-7-fluoro-isoquinolin-3-amine(185 mg, 0.34 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (70.52 mg, 0.07mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (59.18 mg, 0.10mmol) and cesium carbonate (222.12 mg, 0.68 mmol) in 1,4-dioxane (10 mL)was stirred for 12 hours at 90° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(7/3) to afford2-[[6-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(90 mg, 0.12 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=756.

Step 5: tert-butyl6-(2-(bis(4-methoxybenzyl)amino)-3-methylpyridin-4-yl)-3-(6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)-7-fluoroisoquinolin-8-ylcarbamate

A mixture of2-[[6-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.20 mmol), tert-butyl carbamate (696.23 mg, 5.95 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (41.06 mg, 0.040mmol), Brettphos (21.3 mg, 0.040 mmol) and cesium carbonate (258.65 mg,0.79 mmol) in 1,4-dioxane (15 mL) was stirred for 3 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (9/1) to afford tert-butylN-[6-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-8-isoquinolyl]carbamate(110 mg, 0.13 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=457.2.

Step 6:2-(8-amino-6-(2-amino-3-methylpyridin-4-yl)-7-fluoroisoquinolin-3-ylamino)-6-(2,2-difluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[6-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-4-pyridyl]-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-8-isoquinolyl]carbamate(110.0 mg, 0.13 mmol) in 2,2,2-trifluoroacetic acid (10 mL) was stirredat 25° C. for 5 hours. The mixture was concentrated under vacuum. Thecrude product was purified by Prep-HPLC (Atlantis HILIC OBD, 19×150 mm 5um; water (10 mmol/L sodium bicarbonate): CH₃CN=27%-42% B in 7 min) toafford2-[[8-amino-6-(2-amino-3-methyl-4-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(18.3 mg, 0.037 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=497.2; ¹H NMR(400 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.09 (s, 1H), 7.85 (d, J=5.1 Hz, 1H),7.71 (s, 1H), 6.69 (d, J=6.0 Hz, 1H), 6.47 (d, J=5.1 Hz, 1H), 6.34-6.02(m, 3H), 5.99 (s, 1H), 5.82 (s, 2H), 5.05 (s, 2H), 3.95 (t, J=5.7 Hz,2H), 3.85 (td, J=15.5, 4.0 Hz, 2H), 3.10-3.02 (m, 2H), 1.90 (d, J=1.3Hz, 3H).

Example 1872-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-5-methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one(Compound 302)

Step 1: methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate

A solution of 3-bromo-5-methyl-1h-pyrazole (500.0 mg, 3.11 mmol), methylchloroacetate (505.53 mg, 4.66 mmol), tetrabutylammonium iodide (57.3mg, 0.16 mmol) and potassium carbonate (771.43 mg, 5.59 mmol) intetrahydrofuran (10 mL) was stirred for 12 h at 20° C. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(98/2) to afford methyl 2-(3-bromo-5-methyl-pyrazol-1-yl)acetate(671 mg,2.88 mmol) as a white solid. LC/MS (ESI) [M+H]⁺=233.

Step 2: methyl 2-(3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl)acetate

A solution of methyl 2-(3-bromo-5-methyl-pyrazol-1-yl)acetate (20 g,85.81 mmol), 2,2′-Azobis(2-methylpropionitrile)(1.41 g, 8.58 mmol),1-bromo-2,5-pyrrolidinedione(16.80 g, 94.4 mmol) in carbon tetrachloride(400 mL) was stirred at 80° C. for 2 hours. The resulting mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(4/1) to afford methyl 2-[3-bromo-5-(bromomethyl)pyrazol-1-yl]acetate(20 g, 64.11 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=311.

Step 3: 2-bromo-5-methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one

A solution of methyl 2-[3-bromo-5-(bromomethyl)pyrazol-1-yl]acetate (900mg, 2.88 mmol) and methanamine (896.08 mg, 28.85 mmol) intetrahydrofuran (10 mL) was stirred at 25° C. for 2 hours. The mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(4/1) to afford 2-bromo-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrazin-6-one(460 mg, 2.00 mmol) as a white solid. LC/MS (ESI) [M+H]⁺=230.

Step 4: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of 2-bromo-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrazin-6-one(219.55 mg, 0.95 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(400.0 mg, 0.80 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct (164.62 mg, 0.16 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (138.14 mg, 0.24 mmol)and cesium carbonate (518.52 mg, 1.59 mmol) in 1,4-dioxane (60 mL) wasstirred for 12 hours at 100° C. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(10:1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(340 mg, 0.52 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=652.

Step 5: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butyl carbamate (1.83 g, 15.64 mmol), tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(340.0 mg, 0.52 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (107.92 mg, 0.10mmol), Bretthpos (56.0 mg, 0.10 mmol) and cesium carbonate (679.87 mg,2.09 mmol) in 1,4-dioxane (10 mL) was stirred for 3 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (12/88) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(250 mg, 0.34 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=733.

Step 6:2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-5-methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(5-methyl-6-oxo-4,7-dihydropyrazolo[1,5-c]pyrazin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(240.0 mg, 0.33 mmol) in 2,2,2-trifluoroacetic acid (20 mL) was stirredat 25° C. for 2 hours. The mixture was concentrated under vacuum. Thecrude product was purified by Prep-HPLC (Atlantis HILIC OBD, 19×150mm 5um; water (10 mmol/L): CH₃CN=15%-35% B in 7 min) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrazin-6-one(49 mg, 0.11 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=433.3; ¹H NMR(400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.20 (s, 1H), 7.99 (s, 1H), 7.68 (d,J=2.5 Hz, 2H), 6.67 (d, J=6.0 Hz, 1H), 6.08 (s, 2H), 6.05 (s, 1H), 5.24(s, 2H), 4.67 (s, 2H), 4.60 (s, 2H), 3.01 (s, 3H), 1.93 (d, J=1.5 Hz,3H).

Example 188(E)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-4-((1-methyl-1H-pyrazol-4-yl)methylene)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 303)

Step 1: (E)-3-(1-methylpyrazol-4-yl)prop-2-en-1-ol

A solution of tert-butyl (E)-3-(1-methylpyrazol-4-yl)prop-2-enoate (3.0g, 14.41 mmol) and DIBAL-H (43.0 mL, 43.22 mmol) in dichloromethane (100mL) was stirred at 0° C. for 1 hour. The reaction was quenched by addingmethanol. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol (10/1) to afford(E)-3-(1-methylpyrazol-4-yl)prop-2-en-1-ol (800 mg, 5.79 mmol) as acolorless oil. LCMS (ESI) [M+H]⁺=139.

Step 2: (E)-3-(1-methylpyrazol-4-yl)prop-2-enal

A solution of (E)-3-(1-methylpyrazol-4-yl)prop-2-en-1-ol (897 mg, 6.49mmol) and Dess-Martin periodinane (2.75 g, 6.49 mmol) in dichloromethane(30 mL) was stirred at 20° C. for 1 hour. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (95/5) to afford(E)-3-(1-methylpyrazol-4-yl)prop-2-enal (800 mg, 5.87 mmol) as a yellowoil. LCMS (ESI) [M+H]⁺=137.

Step 3: (E)-N-methyl-3-(1-methylpyrazol-4-yl)prop-2-en-1-amine

A solution of (E)-3-(1-methylpyrazol-4-yl)prop-2-enal (794.0 mg, 5.83mmol) and methanamine (543.41 mg, 17.5 mmol) in tetrahydrofuran (20 mL)was stirred at 20° C. for 30 min. Methanol (10 mL) and sodiumborohydride (664.83 mg, 17.5 mmol) were added and stirred at 20° C. for1 hour. The mixture was concentrated under vacuum. The crude product waspurified by reverse phase (C18; water (10 mmol/L sodium bicarbonate) andMeOH (5%-25%)) to afford(E)-N-methyl-3-(1-methylpyrazol-4-yl)prop-2-en-1-amine (412 mg, 2.72mmol) as a colorless oil LCMS (ESI) [M+H]⁺=152.

Step 4:2-(3,5-dibromopyrazol-1-yl)-N-methyl-N-[(E)-3-(1-methylpyrazol-4-yl)allyl]acetamide

A solution of 2-(3,5-dibromopyrazol-1-yl)acetic acid (770 mg, 2.71mmol), (E)-N-methyl-3-(1-methylpyrazol-4-yl)prop-2-en-1-amine (410.1 mg,2.71 mmol) and N,N-diisopropylethylamine (1.05 g, 8.14 mmol) inN,N-dimethylformamide (15 mL) was stirred at 25° C. for 5 min.2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (1.55 g, 4.07 mmol) was added and stirred at 25° C.for 12 hours. The reaction mixture was diluted with ethyl acetate andthen washed with water. The organic phase was dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum. The residue was purified by reverse phase column (C18;Water (10mmol/L sodium bicarbonate) and MeOH (5%-70%) in 20 mins) to afford2-(3,5-dibromopyrazol-1-yl)-N-methyl-N-[(E)-3-(1-methylpyrazol-4-yl)allyl]acetamide(852 mg, 2.04 mmol) as a colorless oil. LCMS (ESI) [M+H]⁺=416.

Step 5:(4E)-2-bromo-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-(3,5-dibromopyrazol-1-yl)-N-methyl-N-[(E)-3-(1-methylpyrazol-4-yl)allyl]acetamide(817 mg, 1.96 mmol), palladium acetate (43.88 mg, 0.20 mmol),triphenylphosphine (102.64 mg, 0.39 mmol), tetrabutylammonium bromide(630.72 mg, 1.96 mmol) and potassium acetate (575.88 mg, 5.88 mmol) inN,N-dimethylformamide (10 mL) was stirred at 90° C. for 12 hours. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford(4E)-2-bromo-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(540 mg, 1.61 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=336.

Step 6:(4Z)-2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of(4E)-2-bromo-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(520 mg, 1.55 mmol),8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (445.03 mg,1.55 mmol), tBuBrettphos Pd G3 (528.37 mg, 0.62 mmol), tBuBrettphos(374.31 mg, 0.77 mmol) and cesium carbonate (1512.72 mg, 4.64 mmol) in1,4-dioxane (20 mL) was stirred at 130° C. for 1 hour. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford(4Z)-2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(305 mg, 0.56 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=543.

Step7: tert-butylN-[7-fluoro-3-[[(4Z)-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate

A mixture of(4Z)-2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(300 mg, 0.55 mmol), tert-butyl carbamate (1.62 g, 13.81 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (114.37 mg, 0.11mmol), Brettphos (88.84 mg, 0.17 mmol) and cesium carbonate (540.34 mg,1.66 mmol) in 1,4-dioxane (15 mL) was stirred at 90° C. for 2 hours.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford tert-butylN-[7-fluoro-3-[[(4Z)-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(100 mg, 0.16 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=624.

Step8:(4E)-2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[7-fluoro-3-[[(4E)-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(95 mg, 0.15 mmol) and 2,2,2-trifluoroacetic acid (3 mL) indichloromethane (3 mL) was stirred at 20° C. for 1 hour. The reactionsolution was concentrated under vacuum. The crude product was purifiedby Prep-HPLC with the following conditions (xBridge Prep C18 OBDColumn19×150 nm]; water (10 mmol/L sodium bicarbonate) and ACN (20%-45%)in 7 min) to afford(4E)-2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-4-[(1-methylpyrazol-4-yl)methylene]-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(13.5 mg, 0.026 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=524; ¹HNMR(400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.20 (s, 1H), 8.50 (d, J=6.0 Hz, 1H),8.44 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.39 (d, J=6.0Hz, 1H), 7.00 (s, 1H), 6.80 (d, J=6.0 Hz, 1H), 6.50 (s, 1H), 6.14 (s,2H), 5.10 (s, 2H), 4.68(s, 2H), 3.89(s, 3H), 2.90 (s, 3H), 2.23 (s, 3H).

Example 1892-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2,2-trifluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 305)

Step 1:2-bromo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a mixture of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (600 mg,2.61 mmol) in N,N-dimethylformamide (25mL) was added sodium hydride(187.78 mg, 60% purity, 4.69 mmol) at 0° C. The reaction was stirred at0° C. for 30 min before 2,2,2-trifluoroethyl trifluoromethanesulfonate(3.03 g, 13.04 mmol) in tetrahydrofuran was added at 0° C. The reactionwas stirred at room temperature for 3 hours before concentrated undervacuum. The residue was purified directly by a reversed phase columnwith 0.5% sodium bicarbonate solution/methanol (60%) to afford2-bromo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(500 mg, 1.60 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=312.

Step 2: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(250 mg, 0.80 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(402.9 mg, 0.80 mmol), tris(dibenzylideneacetone)dipalladium (165.82 mg,0.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (185.2 mg,0.32 mmol) and cesium carbonate (783.43 mg, 2.40 mmol) in 1,4-dioxane(60mL) was stirred at 100° C. for 4 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with petroleum ether/ethyl acetate (2/3) to affordtert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(200 mg, 0.27 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=734.

Step 3: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(280 mg, 0.38 mmol), tert-butyl carbamate (1.12 g, 9.53 mmol),tris(dibenzylideneacetone)dipalladium (78.95 mg, 0.080 mmol), Brettphos(81.77 mg, 0.15 mmol) and cesium carbonate (621.68 mg, 1.91 mmol) in1,4-dioxane (20 mL) was stirred at 90° C. for 2 hours. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(97/3) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(120 mg, 0.15 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=815.

Step 4:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(110 mg, 0.13 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (2 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum. The residue was adjusted to pH 10 withammonia in methanol (7 mol/L). The residue was purified by Prep-HPLC(SunFire Prep C18 OBD Column 19×150 mm 5 um 10 nm; Water (0.1%FA):CAN=22% B to 36% B in 10 min; 25 mL/min) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2,2-trifluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(47.4 mg, 0.092 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=515.2;¹HNMR(300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.11 (s, 1H), 7.99 (s, 1H), 7.73 (s,1H), 7.68 (s, 1H), 6.73 (d, J=6.1 Hz, 1H), 6.07 (s, 2H), 6.01 (s, 1H),5.23 (s, 2H), 5.10 (s, 2H), 4.34-4.24 (m, 2H), 4.00-3.98 (m, 2H),3.07-3.05 (m, 2H), 1.94 (s, 3H).

Example 1902-((8-amino-6-(5-amino-4-chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one;formic acid (Compound 306)

Step 1: 6-benzyloxy-8-chloro-7-fluoro-isoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (100 mg, 0.31mmol), CuI (23.69 mg, 0.12 mmol),3,4,7,8-tetramethyl-1,10-phenanthroline (58.62 mg, 0.25 mmol),phenylmethanol (334.87 mg, 3.1mmol), cesium carbonate (303.25 mg, 0.93mmol) in N,N-dimethylformamide (2 mL) was stirred for 2 hours at 95° C.The mixture was cooled to ambient temperature. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (1/2) to afford6-benzyloxy-8-chloro-7-fluoro-isoquinolin-3-amine (70 mg, 0.23 mmol) asa color solid. LCMS (ESI) [M+I-I]⁺=301.1.

Step 2:2-[(6-benzyloxy-8-chloro-7-fluoro-3-isoquinolyl)amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-bromo-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (60mg, 0.25 mmol), 6-benzyloxy-8-chloro-7-fluoro-isoquinolin-3-amine (74.41mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct(50.88 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(56.83 mg, 0.10 mmol) and cesium carbonate (240.4 mg, 0.74 mmol) in1,4-dioxane (9.6 mL) was stirred for12 hours at 100° C. The mixture wascooled to ambient temperature. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(40/1) to afford2-[(6-benzyloxy-8-chloro-7-fluoro-3-isoquinolyl)amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(65 mg, 0.14 mmol) as a color solid. LCMS (ESI) [M+H]⁺=466.1.

Step 3: tert-butylN-[6-benzyloxy-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of2-[(6-benzyloxy-8-chloro-7-fluoro-3-isoquinolyl)amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(60 mg, 0.13 mmol), tert-butyl carbamate (376.68 mg, 3.22 mmol) ,tris(dibenzylideneacetone)dipalladium-chloroform adduct (26.66 mg, 0.03mmol), BrettPhos (20.71 mg, 0.04 mmol) and cesium carbonate (125.95 mg,0.39 mmol) in 1,4-dioxane (7.5 mL) was stirred at 85° C. for 2 hoursunder nitrogen. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (20/1) to affordtert-butylN-[6-benzyloxy-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(50 mg, 0.092 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=547.1.

Step 4: tert-butylN-[7-fluoro-6-hydroxy-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A solution of tert-butylN-[6-benzyloxy-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(220 mg, 0.40 mmol) and palladium carbon (40 mg, 0.40 mmol) in methanol(20 mL) was stirred under hydrogen (1 atm) at 25° C. for 4 hours. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (5/1) to afford tert-butylN-[7-fluoro-6-hydroxy-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(97.3 mg, 0.21 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=457.1.

Step 5:[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate

To a mixture of [tert-butylN-[7-fluoro-6-hydroxy-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(550 mg, 1.2 mmol), tert-butylN-[7-fluoro-6-hydroxy-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(550 mg, 1.2 mmol) in dichloromethane (20 mL) was added triethylamine(243.39 mg, 2.41 mmol) and trifluoromethanesulfonic (509.93 mg, 1.81mmol) at −60° C. The resulting mixture was stirred for 1 hour at −60° C.The reaction was quenched with water. The resulting mixture wasextracted with dichloromethane, dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum toafford[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate (670 mg, crude)as a yellow oil. LCMS (ESI)[M+H]⁺=589.1.

Step 6:[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid

To a mixture of[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]trifluoromethanesulfonate (670 mg, 1.14 mmol) in 1,4-dioxane (20 mL)wasadded bis(pinacolato)diboron (867.28 mg, 3.42 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (83.3 mg,0.11 mmol) at 90° C. The resulting mixture was stirred for 1 hour at 90°C. The reaction was quenched with water. The resulting mixture wasextracted with dichloromethane, dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum to afford[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid (380 mg, 0.78 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=485.1.

Step 7: tert-butylN-[6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A mixture of 4-chloro-5-iodo-pyridin-3-amine (189.15 mg, 0.74 mmol) and[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronicacid (120 mg, 0.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.28 mg,0.05 mmol), potassium phosphate (157.79 mg, 0.74 mmol), sodium acetate(20.32 mg, 0.25 mmol) in acetonitrile (2 mL)/water (0.2 ml) was stirredfor 1 h at 90° C. The reaction was concentrated under vacuum. The crudewas used in next step directly. LCMS (ESI) [M+H]⁺=567.1

Step 8:2-[[8-amino-6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid

A solution of tert-butylN-[6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(120 mg, 0.21 mmol) and 2,2,2-trifluoroacetic acid (3 mL) indichloromethane (3 mL) was stirred at room temperature for 2 hours. Themixture was concentrated under vacuum. The residue was purified byPrep-HPLC to afford2-[[8-amino-6-(5-amino-4-chloro-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one;formic acid (15.6 mg, 0.030 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=467.1; ¹HNMR (300 MHz, DMSO) δ 9.26 (s, 1H), 9.07 (s, 1H), 8.15(s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 6.80 (d, J=6.0 Hz, 1H), 6.10 (s,2H), 5.98 (s, 1H), 5.79 (s, 2H), 4.97 (s, 2H), 3.83-3.81 (m, 2H),3.18-3.16 (m, 2H), 2.95 (s, 3H).

Example 1912-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(methyl-d3)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 231)

Step 1:2-bromo-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (250 mg,1.09 mmol) and potassium tert-butoxide (243.41 mg, 2.17 mmol) intetrahydrofuran (20 mL) was added iodomethane-D₃ (236.29 mg, 1.63 mmol)at 25° C. The reaction was stirred for 1 hour at 25° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (5/95) to afford2-bromo-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(220 mg, 0.89 mmol) as a white solid. LCMS (ESI) [M+H]⁺=247.

Step 2:2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-bromo-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(220 mg, 0.89 mmol),8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (256.15 mg,0.89 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct(138.22 mg, 0.13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(152.06 mg, 0.18 mmol) and cesium carbonate (870.71 mg, 2.67 mmol) in1,4-dioxane (20 mL) was stirred for 5 hours at 100° C. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (1/10) to afford2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(280 mg, 0.62 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=454.

Step 3: tert-butylN-[7-fluoro-6-(4-methyl-3-pyridyl)-3-[[7-oxo-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(280 mg, 0.62 mmol), tert-butyl carbamate (1.80 g, 15.42 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (127.69 mg, 0.12mmol), BrettPhos (99.38 mg, 0.19 mmol) and cesium carbonate (804.39 mg,2.47 mmol) in 1,4-dioxane (20 mL) was stirred for 2 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (1/10) to afford tert-butylN-[7-fluoro-6-(4-methyl-3-pyridyl)-3-[[7-oxo-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-8-isoquinolyl]carbamate(150 mg, 0.28 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=535

Step 4:2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of tert-butylN-[7-fluoro-6-(4-methyl-3-pyridyl)-3-[[7-oxo-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-8-isoquinolyl]carbamate(120 mg, 0.22 mmol) and 2,2,2-trifluoroacetic acid (2 mL) indichloromethane (2 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum. The resulting residue was purified by reversephase chromatography (acetonitrile 0-40/0.1% ammonia in water) to afford2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-(trideuteriomethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(40.7 mg, 0.09 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=435; ¹HNMR(400 MHz, DMSO) δ 9.27 (s, 1H), 9.08 (s, 1H), 8.50-8.49 (d, J=4.0 Hz,1H), 8.43 (s, 1H), 7.72 (s, 1H), 7.39-7.38 (d, J=4.0 Hz, 1H), 6.79-6.77(d, J=8.0 Hz, 1H), 6.10 (s, 2H), 5.98 (s, 1H), 4.97 (s, 2H), 3.83-3.81(m, 2H), 3.18-3.16 (m, 2H), 2.22 (s, 3H).

Example 192 and Example 193(±)-2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 308),(4R)-2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 309) and(4S)-2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 310)

Step 1:2-bromo-4-hydroxy-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A mixture of2-bromo-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,7-dione (300mg, 1.16 mmol) and NaBH₄ (44.17 mg, 1.16 mmol) in methanol (5 mL) wasstirred at room temperature for 3 hours. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on C18eluting with ACN/water (17%) to afford2-bromo-4-hydroxy-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(200 mg, 0.77 mmol) as a colorless oil. LC/MS (ESI) [M+H]⁺=260

Step 2: 2-bromo-4-fluoro-6-methyl-5, 6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A mixture of2-bromo-4-hydroxy-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(200 mg, 0.77 mmol) and diethylaminosulfur trifluoride (247.9 mg, 1.54mmol) in dichloromethane (20 mL) was stirred at 0° C. for 1 hours. Thereaction was quenched by NaHCO₃ solution. The resulting mixture wasextracted with dichloromethane, dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by reverse phase chromatography (acetonitrile0-40/0.5% sodium bicarbonate in water) to afford2-bromo-4-fluoro-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.57 mmol) as a white solid. LCMS (ESI) [M+H]³⁰ =262.

Step 3: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(4-fluoro-6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of2-bromo-4-fluoro-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(300.0 mg, 1.14 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(575.74 mg, 1.14 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (236.95 mg, 0.23mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (264.65 mg, 0.46mmol) and potassium carbonate (473.9 mg, 3.43 mmol) in 1,4-dioxane (50mL) was stirred for 12 hours at 100° C. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with methanol/dichloromethane(1/10) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(4-fluoro-6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(400 mg, 0.58 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=684.

Step 4: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(4-fluoro-6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(4-fluoro-6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(420 mg, 0.61 mmol), Boc-NH₂ (2.15 g, 18.42 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (127.08 mg, 0.12mmol), Brettphos (65.93 mg, 0.12 mmol) and cesium carbonate (800.55 mg,2.46 mmol) in 1,4-dioxane (10 mL) was stirred for 2 hours at 90° C.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith methanol/dichloromethane (1/10) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(4-fluoro-6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(400 mg, 0.52 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=765

Step 5:(±)-2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 308)

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(4-fluoro-6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(400 mg, 0.52 mmol) and TFA (10 mL, 0.52 mmol)] in dichloromethane (5mL) was stirred at 25° C. for 1 hour. The mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC (Atlantis HILIC OBD,19×150 mm 5 um; water (10 mmol/L): CH₃CN=17%-27% B in 10 min) to afford[2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-4-fluoro-6-methyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(150 mg, 0.32 mmol)] as a yellow solid. LCMS (ESI) [M+H]⁺=465.3; ¹H NMR(400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.25 (s, 1H), 7.99 (s, 1H), 7.67 (s,1H), 6.74 (d, J=6.1 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 6.08 (s, 2H),5.99-5.86 (m, 1H), 5.27-5.18 (m, 3H), 4.81 (d, J=14.9 Hz, 1H), 4.45-4.36(m, 1H), 4.05-3.93 (m, 1H), 3.00 (s, 3H), 1.93 (d, J=1.5 Hz, 3H).

Step 6:(4R)-2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-oneand(4S)-2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

2-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-ylamino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-onewas separated by Chiral-HPLC to afford two isomers: Compoune 309: (18.8mg, 0.041 mmol) as a yellow solid. Retention time: 4.500 min (CHIRALCellulose-SB. 0.46*15 cm; 3 μm; MtBE(0.1% DEA):EtOH=70:30; 1.0 ml/min);LCMS (ESI) [M+H]⁺=465.3; ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.24(s, 1H), 7.98 (s, 1H), 7.66 (s, 2H), 6.73 (d, J=6.1 Hz, 1H), 6.41 (d,J=2.5 Hz, 1H), 6.07 (s, 2H), 6.00-5.83 (m, 1H), 5.27-5.16 (m, 3H), 4.80(d, J=15.0 Hz, 1H), 4.39 (dd, J=35.2, 16.1 Hz, 1H), 4.00 (dd, J=14.6,8.0 Hz, 1H), 2.99 (s, 3H), 1.92 (d, J=1.5 Hz, 3H). Compound 310: (20.9mg, 0.045 mmol) (assumed) as a yellow solid. Retention time: 5.344 min(CHIRAL Cellulose-SB. 0.46*15 cm; 3 μm; MtBE(0.1% DEA):EtOH=70:30; 1.0ml/min); LCMS (53) [M+H]⁺=465.3; ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s,1H), 9.24 (s, 1H), 7.98 (s, 1H), 7.66 (s, 2H), 6.73 (d, J=6.1 Hz, 1H),6.41 (d, J=2.5 Hz, 1H), 6.07 (s, 2H), 5.99-5.83 (m, 1H), 5.27-5.16 (m,3H), 4.80 (d, J=14.9 Hz, 1H), 4.45-4.34 (m, 1H), 4.07-3.96 (m, 1H), 2.99(s, 3H), 1.92 (d, J=1.5 Hz, 3H).

Example 1942-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-4-hydroxy-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(Compound 311)

Step 1:2-bromo-6-methyl-5,6-dihydro-8H-pyrazolo[1,5-g][1,4]diazepine-4,7-dione

A solution of2-bromo-6-methyl-4-methylene-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(1.0 g, 3.9 mmol) in carbon tetrachloride (1 mL), acetonitrile (1 mL)and water (1 mL) was stirred at 25° C. for 10 minutes. RuCl₃ (265.0 mg,1.18 mmol) and sodium periodate (2520 mg, 11.78 mmol) was added. Themixture was stirred at 25° C. for 2 hours. The reaction was quenched byNa₂S₂O₃/NaHCO₃ solution. The resulting mixture was extracted with ethylacetate, dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with EA/PE (20%) to afford2-bromo-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,7-dione (300mg, 1.16 mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=258

Step 2:2-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-6-methyl-5,6-dihydro-8H-pyrazolo[1,5-g][1,4]diazepine-4,7-dione

A mixture of2-bromo-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,7-dione(160.0 mg, 0.62 mmol),8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (178.38 mg,0.62 mmol), t-BuBrettphos (150.04 mg, 0.31 mmol), t-BuBrettphos Pd G3(211.79 mg, 0.25 mmol) and cesium carbonate (606.35 mg, 1.86 mmol) in1,4-dioxane (10 mL) was stirred for 4 hours at 120° C. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withmethanol/dichloromethane (1/10) to afford2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,7-dione(70 mg, 0.15 mmol) as a yellow solid. LC/MS (ESI) [M+H]⁺=465

Step 3:2-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-4-hydroxy-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

To a mixture of2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,7-dione(100 mg, 0.22 mmol) in THF (10 mL) was added methylmagnesium iodide(0.43 mL, 1.29 mmol) in tetrahydrofuran at −78° C. The resultingsolution was stirred for 2 hours at −65° C. The reaction was quenchedwith water. The resulting mixture was extracted with ethyl acetate,dried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with methanol/dichloromethane(1/10) to afford2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4,6-dimethyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(40 mg, 0.083 mmol) as a yellow solid. LC/MS (ESI): [M+H]⁺=481

Step 4: tert-butyl7-fluoro-3-(4-hydroxy-4,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-g][1,4]diazepin-2-ylamino)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4,6-dimethyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(70 mg, 0.15 mmol), Boc-NH₂ (510.9 mg, 4.37 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (30.13 mg, 0.0300mmol), Brettphos (15.63 mg, 0.030 mmol), cesium carbonate (189.8 mg,0.58 mmol) in 1,4-dioxane (5 mL) was stirred for 2 hours at 90° C. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withmethanol/dichloromethane (1/10) to afford tert-butylN-[7-fluoro-3-[(4-hydroxy-4,6-dimethyl-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(40 mg, 0.071 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=562.

Step 5:2-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-4-hydroxy-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one

A mixture of tert-butylN-[7-fluoro-3-[(4-hydroxy-4,6-dimethyl-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(30 mg, 0.050 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroaceticacid (5 mL) was stirred at 25° C. for 2 hours. The mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Atlantis HILIC OBD, 19×150 mm 5 um; water (10 mmol/L): CH₃CN=15%-40% Bin 7 min) to afford2-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)-4-hydroxy-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-g][1,4]diazepin-7(8H)-one(4.3 mg, 0.0093 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=462.3; ¹H NMR(300 MHz, Methanol-d₄) δ 9.16 (s, 1H), 8.50-8.37 (m, 2H), 7.67 (s, 1H),7.42 (d, J=5.2 Hz, 1H), 6.86 (d, J=6.2 Hz, 1H), 6.35 (s, 1H), 5.16 (d,J=15.2 Hz, 1H), 4.96-4.89 (m, 2H), 4.11 (d, J=15.6 Hz, 1H), 3.64 (d,J=15.5 Hz, 1H), 3.15 (s, 3H), 2.32 (s, 3H), 1.61 (s, 3H).

Example 1952-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Compound 312)

Step 1:2-Bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a mixture of2-bromo-4,5,6,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-7-one (900 mg,3.91 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride(281.67 mg, 11.74 mmol) at 0° C. The reaction was then stirred for 0.5hours. 2-iodo-1,1-difluoroethane (3.75 g, 19.56 mmol) inN,N-dimethylformamide (5 mL) was added and stirred at 20° C. for 3hours. The residue was purified directly by a reversed-phase HPLC withMeOH/0.5% sodium bicarbonate in water (5% to 65% in 30 min) to afford2-bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(380 mg, 33% yield) as a white solid. LCMS (ESI) [M+H]⁺=294.1.

Step 2: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(350 mg, 0.70 mmol),2-bromo-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(307 mg, 1.04 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (144 mg, 0.14mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (160 mg, 0.28mmol) and cesium carbonate (680 mg, 2.09 mmol) in 1,4-dioxane (35 mL)was stirred at 100° C. for 3 hours. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by areversed-phase HPLC with MeOH/0.5% sodium bicarbonate in water (5% to75% in 30 min) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(180 mg, 36.1% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=716.4.

Step 3: Tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(180 mg, 0.25 mmol), tert-butyl carbamate (736 mg, 6.28 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (39 mg, 0.04mmol), BrettPhos (27 mg, 0.05 mmol) and cesium carbonate (410 mg, 1.26mmol) in 1,4-dioxane (20 mL) was stirred at 90° C. for 2 hours. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by a reversed-phase HPLC with ACN/0.5% sodiumbicarbonate in water (5% to 65% in 30 min) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(100 mg, 49.9% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=797.5.

Step 4:2-[[8-Amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-3-[[6-(2,2-difluoroethyl)-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(500 mg, 0.63 mmol) and TFA (10 mL) in DCM (5 mL) was stirred at 20° C.for 1.5 hours. The mixture was concentrated under vacuum. The reactionmixture was adjusted to pH 10 with NH₃ in MeOH (7 M). After concentratedunder vacuum, the crude product was purified by Prep-HPLC (XBridge PrepC18 OBD Column19*15 mm 5 um; 10 mmol sodium bicarbonate in water: ACN(20%˜41% in 7 min)) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-(2,2-difluoroethyl)-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(156 mg, 50.3% yield) as a yellow solid. LCMS (ESI) [M+H]⁺=497.3; ¹HNMR(300 MHz, DMSO) δ 9.24 (s, 1H), 9.08 (s, 1H), 7.98 (s, 1H), 7.71 (s,1H), 7.66 (s, 1H), 6.71 (s, 1H), 6.37-5.98 (m, 4H), 5.22 (s, 2H), 5.04(s, 2H), 3.96-3.79 (m, 4H), 3.07-3.03 (m, 2H), 1.92 (s, 3H).

Example 1962-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4-hydroxy-4-(methoxymethyl)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 313)

Step 1:2′-bromo-6′-methyl-5′,6′-dihydrospiro[oxirane-2,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one

A mixture of2-bromo-6-methyl-4-methylene-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(1.0 g, 3.91 mmol) and m-CPBA(2.03 g, 11.73 mmol) in dichloromethane (20mL) was stirred at 25° C. for 12 hours. The reaction was quenched withaqueous Na₂S₂O₃ and NaHCO₃. The resulting mixture was extracted withdichloromethane, dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford2′-bromo-6′-methyl-5′,6′-dihydrospiro[oxirane-2,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one(300 mg, 1.10 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=272.

Step 2:2-bromo-4-hydroxy-4-(methoxymethyl)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of2′-bromo-6′-methyl-5′,6′-dihydrospiro[oxirane-2,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one(300 mg, 1.10 mmol) and sodium methoxide (178 mg, 3.30 mmol) in methanol(5 mL) was stirred for 12 hour at room temperature. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford2-bromo-4-hydroxy-4-(methoxymethyl)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(170 mg, 0.56 mmol) a light yellow solid. LCMS (ESI) [M+H]⁺=304.

Step 3:2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4-(methoxymethyl)-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of 8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine(75.68 mg, 0.26 mmol),2-bromo-4-hydroxy-4-(methoxymethyl)-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(80 mg, 0.26 mmol), t-BuBrettphos Pd G3 (89.85 mg, 0.11 mmol),t-BuBrettphos (63.65 mg, 0.13 mmol) and cesium carbonate (257.25 mg,0.79 mmol) in 1,4-dioxane (4 mL) was stirred at 130° C. for 1 hour. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with Dichloromethane/methanol(10/1) to afford2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4-(methoxymethyl)-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(47 mg, 0.092 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=511.

Step 4: tert-butylN-[7-fluoro-3-[[4-hydroxy-4-(methoxymethyl)-6-methyl-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4-(methoxymethyl)-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(100 mg, 0.20 mmol), tert-butyl carbamate (573.2 mg, 4.89 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (40.51 mg, 0.04mmol), Brettphos (31.47 mg, 0.06 mmol) and cesium carbonate (191.41 mg,0.59 mmol) in 1,4-dioxane (5 mL) was stirred at 90° C. for 3 hours. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-[7-fluoro-3-[[4-hydroxy-4-(methoxymethyl)-6-methyl-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(50 mg, 0.085 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=592.

Step 5:2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4-(methoxymethyl)-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of [tert-butylN-[7-fluoro-3-[[4-hydroxy-4-(methoxymethyl)-6-methyl-7-oxo-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-2-yl]amino]-6-(4-methyl-3-pyridyl)-8-isoquinolyl]carbamate(80 mg, 0.14 mmol) and 2,2,2-trifluoroacetic acid (0.5 mL) indichloromethane (3 mL) was stirred at room temperature for 1 hour. Themixturewas concentrated under vacuum. The residue was adjusted to pH 8with ammonia in methanol (7 mol/L). The crude product was purified byPrep-HPLC (XBridge Prep C18 OBD Column19×150 mm; water (10 mmol/L sodiumbicarbonate): CAN=30%-45% in 7 min) to afford2-[[8-amino-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]amino]-4-hydroxy-4-(methoxymethyl)-6-methyl-5,8-dihydropyrazolo[1,5-d][1,4]diazepin-7-one(11.5 mg, 0.023 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=492. ¹HNMR(400 MHz, DMSO) δ 9.29 (s, 1H), 9.19 (s, 1H), 8.50 (d, J=6.0 Hz, 1H),8.43 (s, 1H), 7.72 (s, 1H), 7.39 (d, J=6.0 Hz, 1H), 6.79 (d, J=6.0 Hz,1H), 6.26 (s, 1H), 6.13 (s, 2H), 5.85 (s, 1H), 5.07-4.84 (m, 2H),4.07-3.65(m, 2H), 3.55-3.43(m, 2H), 3.32 (s, 3H), 2.97 (s, 3H), 2.23 (s,3H).

Example 1972′-((8-amino-7-fluoro-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one(Compound 314)

Step 1:8-chloro-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)isoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (500 mg, 1.55mmol),1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole(500 mg, 2.12 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (113 mg,0.15 mmol) and potassium carbonate (536 mg, 3.88 mmol) in 1,4-dioxane(15 mL) and water (1.5 mL) was stirred at 90° C. for 3 hours. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(96/4) to afford8-chloro-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)isoquinolin-3-amine(517 mg, 1.69 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=305.

Step 2:2-[[8-chloro-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one

A mixture of2-bromo-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one(50 mg, 0.19 mmol),8-chloro-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)isoquinolin-3-amine(56.41 mg, 0.19 mmol), t-BuBrettphos Pd G3 (63.23 mg, 0.07 mmol),t-Bubrettphos (44.79 mg, 0.09 mmol) and cesium carbonate (181.02 mg,0.56 mmol) in 1,4-dioxane (5 mL) was stirred at 130° C. for 1 hour. Themixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(94/6) to afford2-[[8-chloro-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one(27 mg, 0.055 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=494.

Step 3: tert-butylN-[7-fluoro-3-[(6-methyl-7-oxo-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-2-yl)amino]-6-(1,3,5-trimethylpyrazol-4-yl)-8-isoquinolyl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one(136.0 mg, 0.28 mmol), tert-butyl carbamate (806.36 mg, 6.88 mmol),Tris(dibenzylideneacetone)dipalladium-chloroformadduct (56.99 mg, 0.06mmol), Brettphos (44.27 mg, 0.08 mmol) and cesium carbonate (269.27 mg,0.83 mmol) in 1,4-dioxane (5 mL) was stirred at 90° C. for 3 hours. Themixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-[7-fluoro-3-[(6-methyl-7-oxo-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-2-yl)amino]-6-(1,3,5-trimethylpyrazol-4-yl)-8-isoquinolyl]carbamate(65 mg, 0.11 mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=575.

Step 4:2-[[8-amino-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one

A mixture of tert-butylN-[7-fluoro-3-[(6-methyl-7-oxo-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-2-yl)amino]-6-(1,3,5-trimethylpyrazol-4-yl)-8-isoquinolyl]carbamate(87.42 mg, 0.15 mmol) and 2,2,2-trifluoroacetic acid (1.0 mL) indichloromethane (3mL) was stirred at rt for 1 hour. The mixture wasconcentrated under vacuum. The reaction mixture was adjusted to pH 8with ammonia in methanol (7 mol/L). The crude product was purified byPrep-HPLC (XBridge Prep C18 OBD Column19×150 mm; water (10 mmol/L sodiumbicarbonate) and ACN (30%-50%) in 7 min) to afford2-[[8-amino-7-fluoro-6-(1,3,5-trimethylpyrazol-4-yl)-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one(33 mg, 0.07 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=475; ¹H NMR (400MHz, DMSO) δ 9.20 (s, 1H), 8.95 (s, 1H), 7.58 (s, 1H), 6.65 (d, J=6.0Hz, 1H), 5.96 (s, 2H), 5.61 (s, 1H), 5.06 (s, 2H), 3.73-3.70 (m, 5H),2.99 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 1.18-1.16 (m, 2H), 0.95-0.92(m, 2H).

Example 1982-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 315)

Step 1: tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(518 mg, 1.03 mmol),2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(280.27 mg, 1.03 mmol), tris(dibenzylideneacetone)dipalladium (213.19mg, 0.21 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (238.11mg, 0.41 mmol) and cesium carbonate (1.01 g, 3.09 mmol) in 1,4-dioxane(28 mL) was stirred at 100° C. for 15 hours. The reaction was cooled toroom temperature and then concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(280 mg, 0.40 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=694.

Step 2: tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-chloro-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(270 mg, 0.39 mmol), tert-butyl carbamate (1.14 g, 9.72 mmol),tris(dibenzylideneacetone)dipalladium (80.51 mg, 0.08 mmol), Brettphos(83.39 mg, 0.16 mmol) and cesium carbonate (633.97 mg, 1.94 mmol) in1,4-dioxane (40mL) was stirred at 90° C. for 2 hours. The reaction wascooled to room temperature and then concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(150 mg, 0.19 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=775.

Step 3:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(140 mg, 0.18 mmol) and 2,2,2-trifluoroacetic acid (5 mL, 0.18 mmol) indichloromethane (5 mL) was stirred at 20° C. for 1 hours. The crudeproduct was purified by Prep-HPLC (XBridge Shield RP18 OBD Column, 5 μm,19*150 mm; Water (10 mmol/L sodium bicarbonate)=25% B to 45% B in 7 min;25 mL/min) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(36.5 mg, 0.077 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=475.3. ¹ NMR(300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.07 (s, 1H), 7.99 (s, 1H), 7.69 (d,J=8.9 Hz, 2H), 6.72 (d, J=6.1 Hz, 1H), 6.05 (s, 2H), 5.96 (s, 1H), 5.23(s, 2H), 4.97 (s, 2H), 4.61-4.57 (m, 1H), 3.79-3.75 (m, 2H), 2.99-2.96(m, 2H), 1.94 (s, 3H), 1.13 (d, J=6.8 Hz, 6H).

Example 1992′-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one(Compound 316)

Step 1: tert-butylN-[(tert-butoxy)carbonyl]-N-[5-[8-chloro-7-fluoro-3-([3′-methyl-4′-oxo-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-8′-yl]amino)isoquinolin-6-yl]-4-methylpyridin-3-yl]carbamate

A mixture of tert-butylN-[5-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate(200 mg, 0.40 mmol),2-bromo-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one(129 mg, 0.48 mmol), t-BuBrettphos Pd G3 (137 mg, 0.16 mmol),t-Bubrettphos (97 mg, 0.2 mmol), cesium carbonate (391 mg, 1.2 mmol) in1,4-dioxane was stirred at 130° C. for 1 hours. The mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(96/4) to afford tert-butylN-[(tert-butoxy)carbonyl]-N-[5-[8-chloro-7-fluoro-3-([3′-methyl-4′-oxo-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-8′-yl]amino)isoquinolin-6-yl]-4-methylpyridin-3-yl]carbamate(69 mg, 25% yield) as a yellow solid. LCMS(ESI) [M+H]⁺=692.

Step 2: tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6′-methyl-7′-oxo-5′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-2′-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

A mixture of tert-butylN-[(tert-butoxy)carbonyl]-N-[5-[8-chloro-7-fluoro-3-([3′-methyl-4′-oxo-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-8′-yl]amino)isoquinolin-6-yl]-4-methylpyridin-3-yl]carbamate(69 mg, 0.1 mmol), tert-butyl carbamate (293 mg, 2.5 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (21 mg, 0.02mmol), cesium carbonate (98 mg, 0.3 mmol), BrettPhos (22 mg, 0.04 mmol)in 1,4-dioxane (5 mL) was stirred for 2 h at 90° C. The resultingmixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6′-methyl-7′-oxo-5′,6′,7′,8′-tetrahydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-2′-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(39 mg, 50%) as a light yellow solid. LCMS (ESI) [M+H]⁺=773.

Step 3:2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one

A mixture of tert-butylN-tert-butoxycarbonyl-N-[5-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-2-yl)amino]-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate(50 mg, 0.06 mmol) and 2,2,2-trifluoroacetic acid (1.0 mL) indichloromethane was stirred at rt for 1 hour. The mixture wasconcentrated under vacuum. The mixture was adjusted to pH 8 with asolution of NH₃ in methanol. After filtration, the filtrate wasconcentrated under reduced pressure. The crude product was purified byPrep-HPLC (Atlantis HILIC OBD Column 19 mm×150 um; CH₃CN: H₂O (sodiumbicarbonate 10 mmol/L)=28-43% in 8 min) to afford2-[[8-amino-6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-6-methyl-spiro[5,8-dihydropyrazolo[1,5-d][1,4]diazepine-4,1′-cyclopropane]-7-one(8.2 mg, 0.017 mmol) as a yellow solid. LCMS (ESI [M+H]⁺=473; ¹HNMR (400MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.99 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H),7.64 (s, 1H), 6.72 (d, J=6 Hz, 1H), 6.05 (s, 2H), 5.61 (s, 1H), 5.22 (s,2H), 5.06 (s, 2H), 3.73 (s, 2H), 2.99(s, 3H), 1.93(s, 3H), 1.24-1.16 (m,2H), 0.96-0.92 (m, 2H).

Example 2002-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-4-methylene-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 317)

A mixture of tert-butylN-[7-fluoro-3-([6-methyl-4-methylidene-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(20 mg, 0.03 mmol) in HCl in dioxane (2 mL, 4 mol/L) was stirred for 2 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by Prep-HPLC (Atlantis HILIC OBD Column19*150 mm*5 um; Water (0.1% sodium bicarbonate):CH₃CN=25%-41% in 7 min)to afford2-[[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(2.8 mg, 0.006 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=444; ¹HNMR(400 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.17 (s, 1H), 8.50 (d, J=4.0 Hz, 1H),8.42 (s, 1H), 7.65 (s, 1H), 7.38 (d, J=4.0 Hz, 1H), 6.80 (d, J=8.0 Hz,1H), 6.51 (s, 1H), 6.11 (s, 2H), 5.63 (s, 1H), 5.33 (s, 1H), 5.08 (s,2H), 4.41 (s, 2H), 2.91 (s, 3H), 2.21 (s, 3H).

Example 2012-((8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 318)

Step 1: 3,5-dibromo-1H-pyrazole

To a solution of 3,4,5-tribromo-1H-pyrazole (50 g, 164.1 mmol) in THF(750 mL) was added a solution of n-BuLi (2.5 M) in hexane (150 mL) at−65° C. The resulting solution was stirred for 1 h at −65° C. in a dryice bath. The reaction was then quenched by water. The resulting mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(50/1) to afford 3,5-dibromo-1H-pyrazole (20 g, 54%) as a white solid.LCMS (ESI) [M+H]⁺=226.9.

Step 2: Tert-butyl 2-(3,5-dibromo-1H-pyrazol-1-yl)acetate

To a solution of 3,5-dibromo-1H-pyrazole (20 g, 88.55 mmol) inN,N-dimethylformamide (400 mL) was added potassium carbonate (20 g,144.7 mmol), TBAI (1.6 g, 4.33 mmol) and tert-butyl 2-chloroacetate (20g, 132.8 mmol). The resulting solution was stirred for 12 h at roomtemperature. After filtration, the filtrate was concentrated undervacuum. The residue was purified on a silica gel column eluted withdichloromethane/methanol (100/1) to afford tert-butyl2-(3,5-dibromo-1H-pyrazol-1-yl)acetate (18 g, 60%) as a colorless oil.LCMS (ESI) [M+H]⁺=341.0.

Step 3: 2-(3,5-dibromo-1H-pyrazol-1-yl)acetic acid

A solution of tert-butyl 2-(3,5-dibromo-1H-pyrazol-1-yl)acetate (18 g,52.94 mmol) in dichloromethane (10 mL) and 2,2,2-trifluoroacetic acid(100 mL) was stirred for 2 h at 80° C. The resulting mixture wasconcentrated under vacuum to afford2-(3,5-dibromo-1H-pyrazol-1-yl)acetic acid (15 g, crude) as a whitesolid. LCMS (ESI) [M+H]⁺=284.9.

Step 4:2-(3,5-Dibromo-1H-pyrazol-1-yl)-N-methyl-N-(prop-2-en-1-yl)acetamide

A solution of 2-(3,5-dibromo-1H-pyrazol-1-yl)acetic acid (15 g, 52.84mmol), methyl(prop-2-en-1-yl)amine (5.7 g, 80.15 mmol),N,N-diisopropylethylamine (27 g, 208.9 mmol) and HATU (30 g, 78.9 mmol)in N,N-dimethylformamide (500 mL) was stirred for 16 hours at roomtemperature. The resulting mixture was diluted with ethyl acetate andthen washed with sodium chloride solution. The organic phase was driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(2/3) to afford2-(3,5-dibromo-1H-pyrazol-1-yl)-N-methyl-N-(prop-2-en-1-yl)acetamide(16.3 g, 92%) as a yellow oil. LCMS (ESI) [M+H]⁺=338.0.

Step 5:2-Bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-(3,5-dibromo-1H-pyrazol-1-yl)-N-methyl-N-(prop-2-en-1-yl)acetamide (5g, 14.84 mmol), palladium acetate (166 mg, 0.74 mmol),triphenylphosphine (388 mg, 1.48 mmol), TBAB (4.8 g, 14.890 mmol) andpotassium acetate (4.2 g, 42.80 mmol) in N,N-dimethylformamide (100 mL)was stirred for 10 h at 80° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (2/1) to afford2-bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(3.2 g, 84%) as a brown oil. LCMS (ESI) [M+H]⁺=258.1.

Step 6: 5-Bromo-4-methyl-2-(1,3-oxazol-2-yl)pyridine

A mixture of 2,5-dibromo-4-methylpyridine (1.2 g, 4.78 mmol),2-(tributylstannyl)-1,3-oxazole (2.06 g, 5.75 mmol) andtetrakis(triphenylphosphine)palladium (552 mg, 0.48 mmol) in 1,4-dioxane(30 mL) was stirred for 16 hours at 90° C. After filtration, thefiltrate was concentrated under vacuum. The residue was purified on asilica gel column eluted with ethyl acetate/petroleum ether (1/2) toafford 5-bromo-4-methyl-2-(1,3-oxazol-2-yl)pyridine (380 mg, 33%) as alight yellow solid. LCMS (ESI) [M+H^(+])=241.1.

Step 7:4-Methyl-2-(1,3-oxazol-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 5-bromo-4-methyl-2-(1,3-oxazol-2-yl)pyridine (800 mg, 3.35mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.4 g, 33.08 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (244 mg,0.33 mmol) and potassium acetate (820 mg, 8.36 mmol) in 1,4-dioxane (30mL) was stirred for 16 hours at 90° C. After filtration, the filtratewas concentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (1/1) to afford4-methyl-2-(1,3-oxazol-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.2 g, crude) as a light yellow solid. LCMS (ESI) [M+H]⁺=287.1.

Step 8:8-Chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine (550 mg, 1.71mmol),4-methyl-2-(1,3-oxazol-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.2 g, 4.19 mmol), potassium carbonate (825 mg, 5.97 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (125 mg,0.17 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was stirred for 2 hat 90° C. After filtration, the filtrate was concentrated under vacuum.The residue was purified on a silica gel column eluted withdichloromethane/methanol (10/1) to afford8-chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-amine(580 mg 95%) as a brown solid. LCMS (ESI) [M+H]⁺=355.1.

Step 9:2-([8-Chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of8-chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-amine(700 mg, 1.97 mmol),2-bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(1.2 g, 4.69 mmol), 3rd generation t-BuBrettPhos precatalyst (675 mg,0.79 mmol), t-BuBrettPhos (403 mg, 0.83 mmol) and cesium carbonate (3.2g, 9.82 mmol) in 1,4-dioxane (80 mL) was stirred for 1.5 h at 110° C.The mixture was then filtered. The filtrate was concentrated. Afterconcentrated under vacuum, the residue was purified on a silica gelcolumn eluted with dichloromethane/methanol (15:1) to afford2-([8-chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(300 mg, 29%) as a yellow solid. LCMS (ESI) [M+H]⁺=530.3.

Step 10:2-([8-Chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-4,6-dimethyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a mixture of2-([8-chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(300 mg, 0.57 mmol) in methanol (90 mL) and dichloromethane (10 mL) wasadded palladium on carbon (30.12 mg, 0.28 mmol). The reaction wasstirred under hydrogen (2 atom) for 2 h at room temperature and thenfiltered. The filtrate was concentrated under vacuum to afford2-([8-chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-4,6-dimethyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(130 mg, 43%) as a yellow solid. LCMS (ESI) [M+H]⁺=532.3.

Step 11: Tert-butylN-[3-([4,6-dimethyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-8-yl]carbamate

A mixture of2-([8-chloro-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-4,6-dimethyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(100 mg, 0.19 mmol), tert-butyl carbamate (550 mg, 4.70 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (30 mg, 0.03mmol), BrettPhos (20 mg, 0.04 mmol) and cesium carbonate (300 mg, 0.92mmol) in 1,4-dioxane (10 mL) was stirred for 2 h at 90° C. and thenfiltered. After concentrated under vacuum, the residue was purified on asilica gel column eluted with dichloromethane/methanol (10:1) to affordtert-butylN-[3-([4,6-dimethyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-8-yl]carbamate(100 mg, 87%) as a brown oil. LCMS (ESI) [M+H]⁺=6 13.4.

Step 12:2-([8-Amino-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-4,6-dimethyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of tert-butylN-[3-([4,6-dimethyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-8-yl]carbamate(100 mg, 0.16 mmol) in DCM (5 mL) and TFA (5 mL) was stirred for 1.5 hat room temperature. The resulting mixture was concentrated undervacuum. The pH value of the solution was adjusted to 10 with NH₃ inmethanol (7 M). The crude product was purified directly by Prep-HPLC(XBridge Prep C18 OBD Column19*15 mm 5 um; 10 mmol sodium bicarbonate inwater: ACN (50%˜77%) in 8 min) to afford2-([8-amino-7-fluoro-6-[4-methyl-6-(1,3-oxazol-2-yl)pyridin-3-yl]isoquinolin-3-yl]amino)-4,6-dimethyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (22.5 mg, 27%) as a yellowsolid. LCMS (ESI) [M+H]⁺=513.3. ¹HNMR (400 MHz, DMSO) δ 9.29 (s, 1H),9.13 (s, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.74 (s, 1H),7.50 (s, 1H), 6.86-6.84 (m, 1H), 6.17 (s, 2H), 6.04 (s, 1H), 5.13-4.81(m, 2H), 3.84-3.77 (m, 1H), 3.68-3.63 (m, 1H), 3.30-3.26 (m, 1H), 2.97(s, 3H), 2.33 (s, 3H), 1.26 (d, J=7.2 Hz, 3H).

Example 202(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide(Compound 322),(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide(Compound 321),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide(Compound 320) and(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide(Compound 319)

Step 1: methyl(2E)-3-[1-(triphenylmethyl)-1H-imidazol-5-yl]prop-2-enoate

A mixture of 1-(triphenylmethyl)-1H-imidazole-5-carbaldehyde (10 g,29.55 mmol) and methyl 2-(triphenyl-lambda5-phosphanylidene)acetate(9.88 g, 29.55 mmol) in tetrahydrofuran (150 mL) was stirred for 3 h at70° C. The resulting mixture was concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/10) to afford methyl(2E)-3-[1-(triphenylmethyl)-1H-imidazol-5-yl]prop-2-enoate(10 g, 25.38mmol) as a white solid. LCMS (ESI) [M+H]⁺=395

Step 2: trans-methyl2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate

To a mixture of ethyldiphenylsulfanium;trifluoro(lambda2-fluoranidyl)boranuide (15 g, 49.64 mmol) in ethyleneglycol dimethyl ether (100 mL) and dichloromethane (10 mL) was addedlithium diisopropylamide (25 mL, 466.75 mmol) at −78° C. under nitrogen.The reaction was stirred for 30 mins at −78° C. Methyl(2E)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]prop-2-enoate (6.8 g, 17.23mmol) was added. The reaction was stirred for 5 h at −78° C. Thereaction was quenched with ice water. The resulting mixture wasextracted with ethyl acetate and dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by silica gel flash chromatography eluting withdichloromethane/methanol (10/1) to afford trans-methyl2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(3 g, 7.10 mmol) as a white solid. LCMS (ESI) [M+H]⁺=423

Step 3:trans-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid

A mixture of trans-methyl2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(3 g, 7.10 mmol) and LiOH (853 mg, 35.61 mmol) in methanol (20 mL) andwater (20 mL) was stirred for 12 h at room temperature. The reactionmixture was adjusted to pH 5 with hydrogen chloride. The resultingsolution was extracted with of ethyl acetate and the organic layerscombined and concentrated under vacuum to affordtrans-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (1.26 g, 3.08 mmol) as a white solid. LCMS (ESI) [M+H]⁺=409.

Step 4:trans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide

A mixture of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (886 mg,3.07 mmol),trans-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (1.26 g, 3.08 mmol) and Pyridine (5 mL, 62.118 mmol) indichloromethane (50 mL) was added phosphorus oxychloride (1.4 g, 9.13mmol) at 0° C. and then was stirred for 30 min at 0° C. The reaction wasthen quenched with water. The resulting mixture was washed with water.The organic phase was dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by silica gel column with dichloromethane/methanol (10/1) toaffordtrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide(500 mg, 0.73 mmol) as a white solid. LCMS (ESI) [M+H]⁺=678.

Step 5: trans-tert-butylN-(7-fluoro-3-[[2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture of tert-butyl carbamate (5.2 g, 44.38 mmol),trans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide(1.5 g, 2.21 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct (460 mg, 0.44 mmol), BrettPhos (478 mg, 0.89 mmol) and cesiumcarbonate (2.89 g, 8.87 mmol) in dioxane (30 mL) was stirred for 3 h at90° C. under nitrogen. After filtration, the filtrate was concentratedunder vacuum. The residue was purified by silica gel flashchromatography eluting with dichloromethane/methanol (9/1) to affordtert-butylN-(7-fluoro-3-[[(1S,3S)-2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1 g, 1.32 mmol) as a white solid. LCMS (ESI) [M+H]⁺2 759.

Step 6:(1S,2S,3S)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide,(1R,2R,3R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide,(1S,2S,3R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamideand(1R,2R,3S)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide

A mixture of trans-tert-butylN-(7-fluoro-3-[[2-methyl-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1 g, 1.31 mmol) in trifluoroacetic acid (10 mL) was stirred for 1 h atroom temperature. The resulting mixture was concentrated under vacuum.The residue was purified by reverse phase chromatography (acetonitrile0-50/0.1% sodium bicarbonate in water) to afford the mixture (500 mg,1.20 mmol) as a yellow solid. The mixture was separated by Prep-SFC toafford four isomers (Cyclopropane stereochemistry for the isomers:imidazole trans to amide; methyl relative stereochemistry arbitrarilyassigned; All absolute stereochemistry arbitrarily assigned): Compound321: (84.9 mg, 0.20 mmol) as a yellow solid, Retention time:1.25min(CHIRALPAK IC, 3.0*100 mm, 3 μm; MeOH(0.1% DEA); 2 ml/min); LCMS(ESI) [M+H]⁺=417; ¹HNMR (400 MHz, DMSO) δ 11.76(s,1H), 10.68 (s, 1H),9.40 (s, 1H), 8.51 (d, J=4.0 Hz, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.48(s, 1H), 7.40-7.38 (m, 1H), 6.95-6.93 (m, 2H), 6.27 (s, 2H), 2.39-2.32(m, 1H), 2.29-2.27 (m, 1H), 2.19 (s, 3H), 1.75-1.70 (m, 1H), 1.29-1.27(m, 3H). Compound 322: (123.9 mg, 0.29 mmol) as a yellow solid,Retention time:1.47 min(CHIRALPAK IC, 3.0*100 mm, 3 μm; MeOH(0.1% DEA);2 ml/min); LCMS (ESI) [M+H]⁺=417; ¹HNMR (400 MHz, DMSO) δ 11.76(s, 1H),10.68 (s, 1H), 9.40 (s, 1H), 8.51 (d, J=4.0 Hz, 1H), 8.42 (s, 1H), 8.34(s, 1H), 7.48 (s, 1H), 7.40-7.38 (m, 1H), 6.95-6.93 (m, 2H), 6.27 (s,2H), 2.39-2.32 (m, 1H), 2.29-2.27 (m, 1H), 2.19 (s, 3H), 1.75-1.70 (m,1H), 1.29-1.27 (m, 3H). Compound 320: (110.2 mg, 0.26 mmol) as a yellowsolid. Retention time: 1.63 min(CHIRALPAK IC, 3.0*100 mm, 3 μm;MeOH(0.1% DEA); 2 ml/min);LCMS (ESI) [M+H]⁺=417; ¹HNMR (400 MHz, DMSO) δ11.76(s, 1H), 10.68 (s, 1H), 9.40 (s, 1H), 8.51-8.50 (d, J=4.0 Hz, 1H),8.42 (s, 1H), 8.34 (s, 1H), 7.48 (s, 1H), 7.40-7.38 (m, 1H), 6.95-6.93(m, 2H), 6.27 (s, 2H), 2.39-2.32 (m, 1H), 2.29-2.27 (m, 1H), 2.19 (s,3H), 1.75-1.70 (m, 1H), 1.29-1.27 (m, 3H). Compound 319: (168.9 mg, 0.40mmol) as a yellow solid. Retention time:2.20 min(CHIRALPAK IC, 3.0*100mm, 3 μm; MeOH(0.1% DEA); 2 ml/min); LCMS (ESI) [M+H]⁺=417; ¹HNMR (400MHz, DMSO) δ 11.76(s, 1H), 10.68 (s, 1H), 9.40 (s, 1H), 8.51-8.50 (d,J=4.0 Hz, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.48 (s, 1H), 7.40-7.38 (m,1H), 6.95-6.93 (m, 2H), 6.27 (s, 2H), 2.39-2.32 (m, 1H), 2.29-2.27 (m,1H), 2.19 (s, 3H), 1.75-1.70 (m, 1H), 1.29-1.27 (m, 3H).

Example 203(±)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 328)

Step 1: 6-(1-methyl-1H-pyrazol-4-yl)-3-oxabicyclo[3.1.0]hexan-2-one

A solution of (2E)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-en-1-yl2-diazoacetate (100 mg, 0.48 mmol) andtert-butyl[(tert-butyldimethylsilyl)cuprio]dimethylsilane (7.1 mg, 0.024mmol) in toluene (3 mL) was stirred for 2 hours at reflux. The resultingsolution was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with petroleum ether/ethylacetate (2/1) to afford6-(1-methyl-1H-pyrazol-4-yl)-3-oxabicyclo[3.1.0]hexan-2-one (25 mg, 0.14mmol) as a yellow oil. LCMS (ESI) [M+H]⁺=179.1.

Step2:N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

To a solution6-(1-methyl-1H-pyrazol-4-yl)-3-oxabicyclo[3.1.0]hexan-2-one (200 mg,1.12 mmol) in THF (5 mL) was added LiHMDS (1.35 mL, 8.07 mmol) at 0° C.The mixture was then stirred at 0° C. for 30 min. Then8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (287 mg,0.99 mmol) was added. The mixture was stirred for 2 h at roomtemperature. The reaction was then quenched by water. The resultingmixture was extracted with ethyl acetate, dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (1/1) to affordN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(150 mg, 29%) as a yellow solid.

Step 3:N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-[(oxan-2-yloxy)methyl]cyclopropane-1-carboxamide

A mixture ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(150 mg, 0.32 mmol), 3,4-dihydro-2H-pyran (140 mg, 1.66 mmol), TsOH (10mg, 0.058 mmol) in tetrahydrofuran (5 mL) was stirred for 12 h at roomtemperature. The resulting solution was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to affordN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-[(oxan-2-yloxy)methyl]cyclopropane-1-carboxamide(95 mg, 54%) as a yellow solid.

Step 4: tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-pyrazol-4-yl)-3-[(oxan-2-yloxy)methyl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-[(oxan-2-yloxy)methyl]cyclopropane-1-carboxamide(95 mg, 0.17 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol), tert-butyl carbamate(510 mg, 4.35 mmol), BrettPhos (30 mg, 0.056 mmol), cesium carbonate(280 mg, 0.86 mmol), 1,4-dioxane (3 mL) was stirred for 2 h at 90° C.The resulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-pyrazol-4-yl)-3-[(oxan-2-yloxy)methyl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(60 mg, 55%) as a yellow solid.

Step 5:N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

To a solution of tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-pyrazol-4-yl)-3-[(oxan-2-yloxy)methyl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(60 mg, 0.095 mmol) and trifluoroacetic acid (2 mL) in dichloromethane(2 mL) was stirred for 2 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was purified by Prep-HPLC toaffordN-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(7.1 mg, 17%) as a yellow solid. LCMS (ESI) [M+H]⁺=447.3, 2.187 mins, K;¹HNMR (300 MHz, CD₃OD) δ9.303 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.42 (s,1H), 8.36 (s, 1H), 7.51 (s, 1H), 7.44 (s, J=5.1 Hz, 1H), 7.38 (s, 1H),7.00 (d, J=6.0 Hz, 1H), 3.99-3.88 (m, 2H), 3.86 (s, 3H), 2.32-2.24 (m,1H), 2.32 (s, 3H), 2.28-2.24 (m, 1H), 1.93-1.84 (m, 1H).

Example 204 and Example 205(1R,2S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide(Compound 327) and(1S,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide(Compound 326)

Step 1:3-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione

A mixture of 3-oxabicyclo[3.1.0]hexane-2,4-dione (390 mg, 3.48 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (500 mg,1.73 mmol), 4-dimethylaminopyridine (425 mg, 3.47 mmol) in dioxane (10mL) was stirred for 12 h at 120° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gel columnwith dichloromethane/methanol (10/1) to afford3-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione(450mg, 1.18 mmol) as a white solid. LCMS (ESI) [M+H]⁺=382.

Step 2: tert-butylN-(3-[2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture of tert-butyl carbamate (1.22 g, 10.41 mmol),3-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione(200 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct (108 mg, 0.10 mmol), BrettPhos (112 mg, 0.20 mmol), cesiumcarbonate (682 mg, 2.09 mmol) in dioxane (20 mL) was stirred for 2 h at90° C. After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford tert-butylN-(3-[2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(150mg, 0.32 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=463

Step 3: Cis-tert-butylN-(7-fluoro-3-[[2-(hydroxymethyl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a mixture of tert-butylN-(3-[2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(460 mg, 0.99 mmol) in methanol (30 mL) was added sodium borohydride(190 mg, 5.02 mmol). The mixture was stirred for 2 h at roomtemperature. The reaction was quenched with water. The resultingsolution was extracted with ethyl acetate dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by silica gel column withdichloromethane/methanol (10/1) to afford cis-tert-butylN-(7-fluoro-3-[[2-(hydroxymethyl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 0.42 mmol) as a white solid. LCMS (ESI) [M+H]⁺=467.

Step 4:(1R,2S)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)cyclopropane-1-carboxamideand(1S,2R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)cyclopropane-1-carboxamide

A mixture of cis-tert-butylN-(7-fluoro-3-[[2-(hydroxymethyl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 0.42 mmol) in trifluoroacetic acid (5 mL) was stirred for 1 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by reverse phase chromatography(acetonitrile 0-50/0.1% sodium bicarbonate in water) to afford theracemic product (50 mg, 0.13mmol) as a white solid. The racemate productwas separated by Chiral-HPLC to afford two trans-isomers: Compound 327:Retention time: 3.04 min(Repaired Chiral IC, 0.46*10 cm; 5 μm; Hex(0.1%DEA):EtOH=50:50; 1 ml/min); LCMS (ESI) [M+H]⁺=367; ¹HNMR (400 MHz,CD₃OD) δ 9.28 (s, 1H), 8.45-8.44 (d, J=4.0 Hz, 1H), 8.39 (s, 1H), 8.31(s, 1H), 7.42-7.41 (d, J=4.0 Hz, 1H), 6.98-6.96 (d, J=8.0 Hz, 1H),3.86-3.82 (m, 1H), 3.75-3.70 (m, 1H), 2.29 (s, 3H), 2.08-2.02 (m, 1H),1.64-1.59 (m, 1H), 1.15-1.10 (m, 2H). Compound 326: Retention time: 3.86min (Repaired Chiral IC, 0.46*10 cm; 5 μm; Hex(0.1% DEA):EtOH=50:50; 1ml/min); LCMS (ESI) [M+H]⁺=367; ¹HNMR (400 MHz, CD₃OD) δ 9.28 (s, 1H),8.45-8.44 (d, J=4.0 Hz, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.42-7.41 (d,J=4.0 Hz, 1H), 6.98-6.96 (d, J=8.0 Hz, 1H), 3.86-3.82 (m, 1H), 3.75-3.70(m, 1H), 2.29 (s, 3H), 2.08-2.02 (m, 1H), 1.64-1.59 (m, 1H), 1.15-1.10(m, 2H).

Example 2062-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(2,2,2-trifluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 387)

Step 1:2-Bromo-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (1 g, 4.35 mmol) in THF/DMF (40mL/40 mL) was added t-BuOK (1.5 g, 13.4 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (5 g, 21.5 mmol). The resulting solution wasstirred for 16 hours at room temperature. The crude product was purifiedby reversed-phase HPLC (C18 silica gel; 0.5% sodium bicarbonate inwater: MeOH (5%˜70% in 50 min) to afford2-bromo-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(300 mg, 22%) as a colorless oil. LCMS (ESI) [M+H]⁺=312.0.

Step 2:2-[[8-Chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (100 mg,0.35 mmol),2-bromo-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(110 mg, 0.35 mmol), 3rd generation t-BuBrettPhos precatalyst (120 mg,0.14 mmol), t-BuBrettPhos (75 mg, 0.16 mmol), cesium carbonate (570 mg,1.75 mmol) and 1,4-dioxane (12 mL) was stirred for 1 h at 110° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified on a silica gel column eluted with dichloromethane/methanol(15/1) to afford2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (35 mg, 19%) as a yellow solid. LCMS(ESI) [M+H]⁺=519.2.

Step 3: Tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]isoquinolin-8-yl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (150 mg, 0.29 mmol), tert-butylcarbamate (850 mg, 7.26 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (45 mg, 0.043mmol), BrettPhos (30 mg, 0.056 mmol), cesium carbonate (472 mg, 1.45mmol) in 1,4-dioxane (12 mL) was stirred for 2 h at 90° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified on a silica gel column eluted with dichloromethane/methanol(10/1) to afford tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]isoquinolin-8-yl]carbamate (40mg, 23%) as a yellow solid. LCMS (ESI) [M+H]⁺=600.4.

Step 4:2-[[8-Amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[7-oxo-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino]isoquinolin-8-yl]carbamate (40mg, 0.067 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (5mL) was stirred for 2.5 h at room temperature. The resulting mixture wasconcentrated under vacuum. The pH value of the solution was adjusted to10 with NH₃ in methanol (7 M). The crude product was purified directlyby Prep-HPLC (XBridge Prep C18 OBD Column19*15 mm 5 um; 10 mmol sodiumbicarbonate in water: ACN (50%˜77%) in 8 min) to afford2-[[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-(2,2,2-trifluoroethyl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(6.0 mg, 18%) as a yellow solid. LCMS (ESI) [M+H]⁺=500.1; ¹HNMR (300MHz, MeOD) δ 9.14 (s, 1H), 8.44 (d, J=5.7 Hz, 1H), 8.39 (s, 1H), 7.64(s, 1H), 7.41 (d, J=5.7 Hz, 1H), 6.85 (d, J=6.0 Hz, 1H), 6.06 (s, 1H),5.11 (s, 2H), 4.25-4.22 (m, 2H), 4.07-4.03 (m, 2H), 3.19-3.17 (m, 2H),2.30 (s, 3H).

Example 207(1S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 369) and(1R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 370)

Step 1:4-methyl-N-[(1E)-[1-(triphenylmethyl)-1H-imidazol-4-yl]methylidene]benzene-1-sulfonohydrazide

A mixture of 1-(triphenylmethyl)-1H-imidazole-4-carbaldehyde (10 g,29.55 mmol), 4-methylbenzene-1-sulfonohydrazide (11 g, 59.06 mmol) inmethanol (200 mL) and AcOH (0.5 mL) was stirred for 12 h at roomtemperature. After filtration, the solids were collected and washed bymethanol (50 mL) to afford4-methyl-N-[(1E)-[1-(triphenylmethyl)-1H-imidazol-4-yl]methylidene]benzene-1-sulfonohydrazide(10g, 19.76 mmol) as a white solid. LCMS (ESI) [M+H]⁺=507

Step 2:2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate

A mixture methyl (2E)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-enoate (5 g,30.08 mmol),4-methyl-N-[(1E)-[1-(triphenylmethyl)-1H-imidazol-4-yl]methylidene]benzene-1-sulfonohydrazide(18.2 g, 35.92 mmol) in xylene (200 mL) was stirred for 4 h at 150° C.The resulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate to afford methyl2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(1.8g, 3.68 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=489

Step 3:2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid

A mixture of methyl2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(700 mg, 1.43 mmol) and LiOH (172 mg, 7.18 mmol) in water (15 mL) andmethanol (15 mL) was stirred for 12 h at room temperature. The reactionmixture was adjusted to pH 5 with hydrogen chloride (1 N). The resultingmixture was extracted with ethyl acetate and dried with anhydrous sodiumsulfate to afford2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid(500 mg, 1.05 mmol) as a white solid. LCMS (ESI) [M+H]⁺=475

Step 4:N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide

A mixture of2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (500 mg, 1.05 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (302 mg,1.05 mmol) and pyridine (4 mL) in dichloromethane (20 mL) was addedphosphorus oxychloride (480 mg, 3.13 mmol) at 0° C. The resultingsolution was stirred for 30 min at 0° C. The reaction was concentratedunder vacuum. The residue was purified by silica gel column withdichloromethane/methanol (10/1) to affordtrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide(350 mg, 0.47 mmol) as a white solid. LCMS (ESI) [M+H]⁺=744.

Step 5: tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide(250 mg, 0.33 mmol), tert-butyl carbamate (787 mg, 6.71 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (70 mg, 0.06mmol), BrettPhos (72 mg, 0.13 mmol) and cesium carbonate (438 mg, 1.34mmol) in dioxane (20 mL) was stirred for 3 h at 90° C. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(120 mg, 0.14 mmol) as a white solid. LCMS (ESI) [M+H]⁺=825.

Step 6:(1R,3S)-N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamideand(1S,3R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

A mixture of tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-pyrazol-4-yl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(100 mg, 0.12 mmol) in trifluoroacetic acid (5 mL) was stirred for 1 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by reverse phase chromatography(acetonitrile 0-50/0.1% FA in water) to afford the racemic product (20mg, 0.04 mmol) as a yellow solid. The racemic product was separated byChiral-HPLC to afford two isomers: (Cyclopropane stereochemistry for theisomers: pyrazole trans to amide; imidazole relative stereochemistryunknown; All absolute stereochemistry arbitrarily assigned) Compound370: Retention time:4.99 min(CHIRALPAK ID-3, 0.46*10 cm; 3 μm; MtBE(0.1%DEA):EtOH=50:50; 1 ml/min); LCMS (ESI) [M+H]⁺=483; ¹HNMR (400 MHz,CD₃OD) δ 9.33(s, 1H), 8.48 (d, J=4.0 Hz, 1H), 8.42-8.40 (m, 2H), 7.56(s, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.27 (s, 1H), 7.12 (s, 1H), 7.03 (s,1H), 6.77 (s, 1H), 3.73 (s, 3H), 2.90-2.86 (m, 1H), 2.79-2.76 (m, 1H),2.71-2.69 (m, 1H), 2.32 (s, 3H); Compound 369: Retention time: 5.98min(CHIRALPAK ID-3, 0.46*10 cm; 3 μm; MtBE(0.1% DEA):EtOH=50:50; 1ml/min); LCMS (ESI) [M+H]⁺=483; ¹HNMR (400 MHz, CD₃OD) δ 9.33(s, 1H),8.48 (d, J=4.0 Hz, 1H), 8.42-8.40 (m, 2H), 7.56 (s, 1H), 7.45 (d, J=4.0Hz, 1H), 7.27 (s, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 6.77 (s, 1H), 3.73(s, 3H), 2.90-2.86 (m, 1H), 2.79-2.76 (m, 1H), 2.71-2.69 (m, 1H), 2.32(s, 3H)

Example 208 and Example 209(±)-(1R,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide(Compound 343);(1R,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide (Compound 344) and(1S,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide (Compound 345)

Step 1: ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-6-carboxylate

To a solution of (2-ethoxy-2-oxoethyl)dimethylsulfanium bromide (60 g,261.85 mmol) and cesium carbonate (101 g, 309.98 mmol) inN,N-dimethylformamide (300 mL) was stirred for 20 min at 20° C.2,5-dihydrofuran-2-one (20 g, 237.88 mmol) was added and the mixture wasstirred for an additional 15 hours at 20° C. The reaction was quenchedby water. The resulting solution was extracted with ethyl acetate, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(3/7) to afford ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-6-carboxylate (3g, 7%) as a white solid. LCMS (ESI) [M+H]⁺=171.

Step 2: ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-(hydroxymethyl)cyclopropane-1-carboxylate

To a solution of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (6.1 g,21.20 mmol) in tetrahydrofuran (150 mL) was added LiHMDS (18 mL, 107.57mmol) and then stirred for 1 hour at −78° C. Ethyl2-oxo-3-oxabicyclo[3.1.0]hexane-6-carboxylate (4.5 g, 26.45 mmol) wasadded and the mixture was stirred for another 15 hours at 20° C. Theresulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (49/1) to afford ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-(hydroxymethyl)cyclopropane-1-carboxylate(3.1 g, 26%) as a yellow solid. LCMS (ESI) [M+H]⁺=458.

Step 3: ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-[(methanesulfonyloxy)methyl]cyclopropane-1-carboxylate

To a solution of ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-(hydroxymethyl)cyclopropane-1-carboxylate(1.4 g, 3.06 mmol) in dichloromethane (20 mL) was added triethylamine(927 mg, 9.161 mmol) and methanesulfonyl chloride (703 mg, 6.14 mmol)and then stirred for 15 min at 0° C. The resulting solution wasconcentrated under vacuum to afford ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-[(methanesulfonyloxy)methyl]cyclopropane-1-carboxylate(2 g, crude) as a brown solid. LCMS (ESI) [M+H]⁺=536.

Step 4: ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-[(dimethylamino)methyl]cyclopropane-1-carboxylate

To a solution of ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-[(methanesulfonyloxy)methyl]cyclopropane-1-carboxylate(3.6 g, 6.72 mmol) and dimethylamine in methanol(160 mL) was stirred for36 h at 20° C. The resulting mixture was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (24/1) to afford ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-[(dimethylamino)methyl]cyclopropane-1-carboxylate(1.85 g, 57%) as a yellow solid. LCMS (ESI) [M+H]⁺=485.

Step 5: ethyl2-[(8-[[(tert-butoxy)carbonyl]amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)carbamoyl]-3-[(dimethylamino)methyl]cyclopropane-1-carboxylate

A mixture of ethyl2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]-3-[(dimethylamino)methyl]cyclopropane-1-carboxylate(592 mg, 1.22 mmol), tert-butyl carbamate (3.57 g, 30.475 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (253 mg, 0.244mmol), BrettPhos (262 mg, 0.49 mmol), cesium carbonate (1.99 g, 6.11mmol) in 1,4-dioxane (20 mL) was stirred for 15 h at 90° C. The mixturewas then filtered. The filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1) to afford ethyl2-[(8-[[(tert-butoxy)carbonyl]amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)carbamoyl]-3-[(dimethylamino)methyl]cyclopropane-1-carboxylate(280 mg, 41%) as a brown solid. LCMS (ESI) [M+H]⁺=566.

Step 6: tert-butylN-(3-[[2-[(dimethylamino)methyl]-3-(hydroxymethyl)cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of ethyl2-[(8-[[(tert-butoxy)carbonyl]amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)carbamoyl]-3-[(dimethylamino)methyl]cyclopropane-1-carboxylate(280 mg, 0.49 mmol) in dichloromethane (5 mL) was added DIBAl—H (1.98mL, 11.81 mmol). The mixture was stirred for 1 hour at −78° C. Thereaction was quenched by methanol. The resulting mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol (7/3)to afford tert-butylN-(3-[[2-[(dimethylamino)methyl]-3-(hydroxymethyl)cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(80 mg, 31%) as a brown solid. LCMS (ESI) [M+H]⁺=524.

Step 7: tert-butylN-(3-[[2-[(dimethylamino)methyl]-3-[(methanesulfonyloxy)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of tert-butylN-(3-[[2-[(dimethylamino)methyl]-3-(hydroxymethyl)cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(70 mg, 0.13 mmol) in dichloromethane (5 mL) was added triethylamine (42mg, 0.42 mmol), methanesulfonyl chloride (31 mg, 0.27 mmol). Theresulting solution was stirred for 15 min at 0° C. The resultingsolution was concentrated under vacuum to afford tert-butylN-(3-[[2-[(dimethylamino)methyl]-3-[(methanesulfonyloxy)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(90 mg, crude) as a brown solid. LCMS (ESI) [M+H]⁺=602.

Step 8: tert-butylN-(3-[[2-(cyanomethyl)-3-[(dimethylamino)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a mixture of tert-butylN-(3-[[2-[(dimethylamino)methyl]-3-[(methanesulfonyloxy)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(90 mg, 0.150 mmol) and NaCN (15 mg, 0.31 mmol) in DMSO (5 mL) wasstirred for 1 h at 50° C. The reaction was quenched by water. Theresulting solution was extracted with ethyl acetate, dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford ert-butylN-(3-[[2-(cyanomethyl)-3-[(dimethylamino)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(50 mg, 63%) as a brown solid. LCMS (ESI) [M+H]⁺=533.

Step 9:(1R,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamideand(1S,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide

To a solution of tert-butylN-(3-[[(1R,2S,3S)-2-(cyanomethyl)-3-[(dimethylamino)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(48 mg, 0.090 mmol) and trifluoroacetic acid (5 mL) in dichloromethane(5 mL) was stirred for 1 h at 20° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions (Kinetex EVO C18 Column, 30*150,5 um; Water (10mmol/L sodium bicarbonate) and ACN (15% to 35%) in 10 min) to afford(±)-(1R,2S,3S)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(cyanomethyl)-3-[(dimethylamino)methyl]cyclopropane-1-carboxamide(2.4 mg, 6%) as a yellow solid. LCMS (ESI) [M+H]⁺=433.2; ¹HNMR (300 MHz,DMSO-d₆) δ 10.84 (s, 1H), 9.41 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.42 (s,1H), 8.29 (s, 1H), 7.39 (d, J=5.1Hz, 1H), 6.94 (d, J=6.2 Hz, 1H), 6.29(s, 2H), 2.84-2.72 (m, 2H), 2.46 (d, J=6.7 Hz, 2H), 2.21 (s, 3H), 2.13(s, 7H), 1.60 (dd, J=6.5, 5.0 Hz, 1H), 1.51-1.40 (m, 1H). The racemicproduct was separated by SFC to afford two isomers. Compound 344 (5.1mg, 34%) as a yellow solid. Retention time: 3.652 min (CHIRALPAK IF,2*25 cm, 5 μm; MTBE and 20.0% ethanol (8 mmol/L NH₃. H₂O) in 23 min);LCMS (ESI) [M+H]⁺=433.2; ¹HNMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.41(s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 7.39 (d,J=5.1 Hz, 1H), 6.94 (d, J=6.2 Hz, 1H), 6.29 (s, 2H), 2.84-2.72 (m, 2H),2.46 (d, J=6.7 Hz, 2H), 2.21 (s, 3H), 2.13 (s, 7H), 1.60 (dd, J=6.5, 5.0Hz, 1H), 1.51-1.40 (m, 1H). Compound 345: (5.4 mg, 36%) as a yellowsolid. Retention time: 4.805 min (CHIRALPAK IF, 2*25 cm, 5 μm; MTBE and20.0% ethanol (8 mmol/L NH₃. H₂O) in 23 min); LCMS (ESI) [M+H]⁺=433.2;¹HNMR (300MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.41 (s, 1H), 8.50 (d, J=5.0Hz, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 7.39 (d, J=5.1 Hz, 1H), 6.94 (d,J=6.2 Hz, 1H), 6.29 (s, 2H), 2.84-2.72 (m, 2H), 2.46 (d, J=6.7 Hz, 2H),2.21 (s, 3H), 2.13 (s, 7H), 1.60 (dd, J=6.5, 5.0 Hz, 1H), 1.51-1.40 (m,1H).

Example 210(1S,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-(1H-imidazol-4-yl)cyclopropane-1-carboxamide(Compound 324) and(1R,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-(1H-imidazol-4-yl)cyclopropane-1-carboxamide(Compound 323)

Step 1: dimethyl3-(1-trityl-1H-imidazol-4-yl)cyclopropane-1,2-dicarboxylate

A mixture of 1,4-dimethyl (2E)-but-2-enedioate (10 g, 69.38 mmol),4-methyl-N-[(1E)-[1-(triphenylmethyl)-1H-imidazol-4-yl]methylidene]benzene-1-sulfonohydrazide(2.85 g, 5.63 mmol) and potassium carbonate (4.09 g, 29.59 mmol) inxylene (150 mL) was stirred for 1 h at 150° C. The mixture was thenfiltered and concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford (±)-dimethyl(1S,2S)-3-(1-trityl-1H-imidazol-4-yl)cyclopropane-1,2-dicarboxylate (4g, 24%) as a light yellow solid. LCMS (ESI) [M+H]⁺=467.

Step 2:2-(methoxycarbonyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid

A mixture of 1,2-dimethyl3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1,2-dicarboxylate(3.2 g, 6.85 mmol) and LiOH.H₂O (288 mg, 6.86 mmol) in tetrahydrofuran(30 mL) and methanol (10 mL) was stirred for 2 h at room temperature.The mixture was concentrated under vacuum. The residue was diluted withwater and the pH value of the solution was adjusted to 4 with hydrogenchloride (1.0 mol/L). The resulting mixture was extracted with 3×100 mLof dichloromethane. The organic layers combined and dried over anhydroussodium sulfate and filtered. The resulting mixture was concentratedunder vacuum to afford2-(methoxycarbonyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (1.2 g, 39%) as a white solid. LCMS (ESI) [M+H]⁺=453.

Step 3: methyl2-(hydroxymethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate

To a solution of2-(methoxycarbonyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (3.0 g, 6.63 mmol) in dichloromethane (40 mL) was added BH₃-Me₂S (2mL, 21.09 mmol). The solution was stirred for 2 h at room temperature.The reaction was then quenched by methanol. The mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (10/1) to afford methyl2-(hydroxymethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(1.5 g, 52%) as a white solid. LCMS (ESI) [M+H]⁺=439.

Step 4: methyl2-[(methanesulfonyloxy)methyl]-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate

To a solution of methyl2-(hydroxymethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(537 mg, 1.23 mmol) and triethylamine (371 mg, 3.67 mmol) indichloromethane (10 mL) was added methanesulfonyl chloride (281 mg, 2.45mmol) at 0° C. The solution was stirred for 15 min at 0° C. The reactionwas then quenched by water. The resulting solution was extracted withdichloromethane. The organic layers were dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum toafford methyl2-[(methanesulfonyloxy)methyl]-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(500 mg, 79%) as light yellow oil. LCMS (ESI) [M+H]⁺=517.

Step 5: methyl(2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate

A mixture of methyl2-[(methanesulfonyloxy)methyl]-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(620 mg, 1.20 mmol) and NaCN (118 mg, 2.41 mmol) in dimethyl sulphoxide(10 mL) was stirred for 1 h at 50° C. The reaction was diluted withethyl acetate. The resulting mixture was washed with water. The organicphase was dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(95/5) to afford methyl2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(440mg, 82%) as a light yellow solid. LCMS (ESI) [M+H]⁺=448.

Step 6:(1R,2S,3S)-2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid

A mixture of methyl2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(400 mg, 0.89 mmol) and sodium hydroxide (107 mg, 2.68 mmol) in ethanol(10 mL), tetrahydrofuran (10 mL) and water (10 mL) was stirred for 12 hat room temperature. The mixture was concentrated under vacuum. Theresulting solution was diluted with water. The pH value of the solutionwas adjusted to 4 with hydrogen chloride (1.0 mol/L). The solution wasextracted with dichloromethane. The organic layers were dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (320 mg, 83%) as a light yellow solid. LCMS (ESI) [M+H]⁺=434.

Step7: tert-butylN-(3-[[(2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (377 mg, 0.87 mmol), tert-butylN-[3-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(320 mg, 0.87 mmol) and pyridine (1 mL) in dichloromethane (10 mL) wasadded POCl₃ (405 mg, 2.64 mmol). The mixture was stirred for 30 min at0° C. The reaction was then quenched by water and then extracted withethyl acetate. The organic layers were dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol (10/1) to afford tert-butylN-(3-[[2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamateb(500 mg, 73%) as yellow oil. LCMS (ESI) [M+H]⁺=784.

Step8:(1R,2S,3S)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(cyanomethyl)-3-(1H-imidazol-4-yl)cyclopropane-1-carboxamideand(1S,2R,3R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(cyanomethyl)-3-(1H-imidazol-4-yl)cyclopropane-1-carboxamide

A mixture of tert-butylN-(3-[[2-(cyanomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(600 mg, 0.77 mmol) in dichloromethane (5 mL) and 2,2,2-trifluoroaceticacid (5 mL) was stirred for 1 h at room temperature. The mixture wasconcentrated under vacuum and then diluted with dichloromethane. The pHvalue of the solution was adjusted to 8 with ammonia in methanol (7mol/L). The crude product was purified by Prep-HPLC (Kinetex EVO C18Column, 30*150, 5 μm; Water (10 mmol/L sodium bicarbonate) and ACN (20%ACN up to 35% in 7 min) to afford the racemic product. The racemicproduct was purified by Chiral-HPLC to afford two enantiomers. Compound323: (16.7 mg, 5%) as a light yellow solid. LCMS (ESI) [M+H]⁺=784. ¹HNMR(400 MHz, DMSO) δ 11.86 (s, 1H), 10.77 (s, 1H), 9.39 (s, 1H), 8.50 (d,J=6.0 Hz, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 7.39 (d, J=6.0Hz, 1H), 6.89 (d, J=6.0 Hz, 1H), 6.80 (s, 1H), 6.29 (s, 2H), 2.97-2.82(m, 2H), 2.47-2.41 (m, 2H), 2.38-2.20 (m, 4H). Compound 324: (13.8 mg,4%) as a light yellow solid. LCMS (ESI) [M+H]⁺=784. ¹HNMR (400 MHz,DMSO) δ 11.86 (s, 1H), 10.77 (s, 1H), 9.39 (s, 1H), 8.50 (d, J=6.0 Hz,1H), 8.41 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 7.39 (d, J=6.0 Hz, 1H),6.89 (d, J=6.0 Hz, 1H), 6.80 (s, 1H), 6.29 (s, 2H), 2.97-2.82 (m, 2H),2.47-2.41 (m, 2H), 2.38-2.20 (m, 4H).

Example 2112-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 229)

Step 1: tert-butylN-[(tert-butoxy)carbonyl]-N-[5-[8-chloro-7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)isoquinolin-6-yl]-4-methylpyridin-3-yl]carbamate

A mixture of2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (25mg, 0.10 mmol), tert-butylN-[5-(3-amino-8-chloro-7-fluoroisoquinolin-6-yl)-4-methylpyridin-3-yl]-N-[(tert-butoxy)carbonyl]carbamate(50 mg, 0.099 mmol), tris(dibenzylideneacetone)dipalladium-chloroformadduct (21 mg, 0.020 mmol), XantPhos (23 mg, 0.040 mmol), cesiumcarbonate (81 mg, 0.25 mmol) in 1,4-dioxane (4 mL) was stirred for 15 hat 100° C. The reaction solution was cooled to room temperature and thenfiltrated. The filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with petroleumether/ethyl acetate (1/1) to afford tert-butylN-[(tert-butoxy)carbonyl]-N-[5-[8-chloro-7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)isoquinolin-6-yl]-4-methylpyridin-3-yl]carbamate(20 mg, 0.030 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=666.

Step 2: tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate

A mixture of tert-butylN-[(tert-butoxy)carbonyl]-N-[5-[8-chloro-7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)isoquinolin-6-yl]-4-methylpyridin-3-yl]carbamate(60 mg, 0.090 mmol), tert-butyl carbamate (264 mg, 2.25 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (19 mg, 0.018mmol), BrettPhos (20 mg, 0.037 mmol), cesium carbonate (147 mg, 0.45mmol) in 1,4-dioxane (15 mL) was stirred for 2 h at 90° C. The reactionsolution was cooled to room temperature and then filtrated. The filtratewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(1/1) to afford tert-butyl(tert-butoxycarbonyl)(5-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methylpyridin-3-yl)carbamate(50 mg, 0.067 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=747.

Step 3:2-[[8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)-7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)isoquinolin-8-yl]carbamate(290 mg, 0.39 mmol) and trifluoroacetic acid (10 mL) in dichloromethane(3 mL) was stirred for 1 h at 20° C. The resulting mixture wasconcentrated under vacuum. The pH value of the solution was adjusted to11 with ammonia in methanol (7 mol/L). The crude product was purified byPrep-HPLC with the following conditions (XBridge Shield RP18 OBD Column,30*150 mm, 5 um; water (10 mmol/L sodium bicarbonate) and ACN (10% ACNup to 30% in 10 min) to afford2-[[8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (34.1 mg, 20%) as a yellow solid.LCMS (ESI) [M+H]⁺=447.2; ¹HNMR (300MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.07(s, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 6.72 (d, J=6.1 Hz,1H), 6.07 (s, 2H), 5.99 (s, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 3.84 (t,J=5.7 Hz, 2H), 3.05 (t, J=5.6 Hz, 2H), 2.96 (s, 3H), 1.94 (d, J=1.5 Hz,3H).

Example 212(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide(Compound 332),(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide(Compound 331), (1S,2S,3S)—N-(8-amino-7-fluoro-6-(4methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide(Compound 330) and(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5yl)cyclopropane-1-carboxamide (assumed) (Compound 329)

Step 1: 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of 5-iodo-1H-pyrazole (10 g, 51.55 mmol), 3,4-dihydro-2H-pyran(13 g, 154.55 mmol), TsOH (443 mg, 2.57 mmol) in ethyl acetate (200 mL)was stirred for 3 h at 80° C. The resulting mixture was washed withwater. The organic phase was dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/petroleum ether (3/7) to afford3-iodo-1-(oxan-2-yl)-1H-pyrazole (7.0 g, 25.18 mmol) as a white solid.LCMS (ESI) [M+H]⁺=279.

Step 2: (E)-methyl3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acrylate

A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole (5 g, 17.98 mmol), methylprop-2-enoate (4.64 g, 53.90 mmol), palladium acetate (604 mg, 2.69mmol), tri-o-tolyl phopine (1.09 g, 3.58 mmol), triethylamine (2.725 g,26.93 mmol) in N,N-dimethylformamide (100 mL) was stirred for 12 h at110° C. The resulting solution was diluted with ethyl acetate and thenwashed with water. The organic phase was dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (15/85) to afford methyl(2E)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]prop-2-enoate (2.7 g, 11.44 mmol)as a yellow solid. LCMS (ESI) [M+H]⁺=237.

Step 3: methyl2-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)cyclopropanecarboxylate

A mixture of methyl (2E)-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]prop-2-enoate(2.7 g, 11.43 mmol), ethyldiphenylsulfanium trifluoroborane fluoride(10.37 g, 34.31 mmol), lithium diisopropylamide (20 mL, 373.40 mmol) indichloromethane (30 mL) and ethylene glycol dimethyl ether (150 mL) wasstirred for 5 hours at room temperature. The reaction was then quenchedby water. The resulting solution was extracted with ethyl acetate, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(4/6) to afford methyl2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane-1-carboxylate(1.5 g, 5.66 mmol) as yellow oil. LC/MS (ESI) [M+H]⁺=265

Step 4:2-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)cyclopropanecarboxylicacid

A mixture of methyl2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane-1-carboxylate(1.45 g, 5.49 mmol), LiOH (659 mg, 27.52 mmol) in tetrahydrofuran (15mL) and water (15 mL) was stirred for 12 hours at room temperature. Theresulting mixture was washed with ethyl acetate. The water phase wasadjusted to pH 3 with hydrogen chloride (1 mol/L). The resultingsolution was extracted with ethyl acetate, dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum toafford2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane-1-carboxylic acid(1.3 g, 5.18 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=251

Step 5:N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)cyclopropanecarboxamide

A mixture of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (1.5 g,5.21 mmol),2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane-1-carboxylic acid(1.3 g, 5.19 mmol), POCl₃ (1.6 g, 10.44 mmol), pyridine (5 mL, 62.12mmol) in dichloromethane (30 mL) was stirred for 30 minutes at roomtemperature. The reaction was then quenched by water. The resultingsolution was extracted with dichloromethane, dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (2/1) to afford(1S,3S)—N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane-1-carboxamide(1.26 g, 2.42 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=520.

Step 6: tert-butyl7-fluoro-3-(2-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3yl)cyclopropanecarboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane-1-carboxamide(1.3 g, 2.50 mmol), tert-butyl carbamate (8.79 g, 75.05 mmol), BrettPhos(269 mg, 0.50 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (518 mg, 0.50mmol, Cesium carbonate (3.27 g, 10.02 mmol) in 1,4-dioxane (160 mL) wasstirred for 2 hours at 90° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(9/1) to affordtert-butylN-(7-fluoro-3-[[2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(480 mg, 0.80 mmol) as a yellow solid. LC/MS (ESI) [M+H]⁺=601.

Step 7:(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropanecarboxamide(assumed),(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropanecarboxamide(assumed),(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropanecarboxamide(assumed) and(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropanecarboxamide(assumed)

A mixture of tert-butylN-(7-fluoro-3-[[2-methyl-3-[1-(oxan-2-yl)-1H-pyrazol-3-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(480 mg, 0.80 mmol), methanol (2 mL, 49.40 mmol) in HCl/dioxane (8 mL)was stirred for 10 h at room temperature. The resulting solution wasconcentrated uncer vacuum. The crude product was purified by Prep-HPLC(C18 silica gel; 0.5% sodium bicarbonate in water:ACN=30%-40% in 7 min)to afford the mixture (150 mg, 0.36 mmol). The mixture was separated byChiral-HPLC to afford four isomers (Cyclopropane stereochemistry foreach isomer: pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarilyassigned): Compound 332: (16.7 mg, 0.040 mmol) as a yellow solid.Retention time: 2.289 min (Repaired Chiral IC. 0.46*10 cm; 5 μm;MtBE(0.1% DEA):IPA=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=417.3; ¹H NMR(400 MHz, DMSO-d₆) δ 12.73-12.49 (m, 1H), 10.82-10.77 (m, 1H), 9.42 (s,1H), 8.52 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.61-7.35 (m,2H), 6.96 (d, J=6.1 Hz, 1H), 6.32 (s, 2H), 6.06-5.97 (m, 1H), 2.42-2.29(m, 2H), 2.22 (s, 3H), 1.73 (s, 1H), 1.29 (d, J=6.1 Hz, 3H). Compound331: (36.7 mg, 0.088 mmol) as a yellow solid. Retention time: 2.917 min(Repaired Chiral IC. 0.46*10 cm; 5 μm; MtBE(0.1% DEA):IPA=70:30; 1.0ml/min); LCMS (ESI) [M+H]⁺=417.2; ¹H NMR (400 MHz, DMSO-d₆) δ12.77-12.59 (m, 1H), 10.82 (s, 1H), 9.43 (s, 1H), 8.51 (d, J=5.0 Hz,1H), 8.44 (s, 1H), 8.33 (s, 1H), 7.66-7.40 (m, 2H), 6.94 (d, J=6.0 Hz,1H), 6.32 (s, 2H), 6.14-6.01 (m, 1H), 2.49-2.24 (m, 3H), 2.22 (s, 2H),1.70-1.64 (m, 1H), 1.1-0.9 (m, 3H). Compound 330: (17.8 mg, 0.043 mmol)as a yellow solid. Retention time: 3.720 min (Repaired Chiral IC.0.46*10 cm; 5 μm; MtBE(0.1% DEA):IPA=70:30; 1.0 ml/min); LCMS (ESI)[M+H]⁺=417.2; ¹H NMR (400 MHz, DMSO-d₆) δ 12.73-12.49 (m, 1H),10.82-10.77 (m, 1H), 9.42 (s, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.44 (s, 1H),8.36 (s, 1H), 7.61-7.35 (m, 2H), 7.09-6.82 (m, 1H), 6.32 (s, 2H),6.15-5.72 (m, 1H), 2.43-2.32 (m, 2H), 2.22 (s, 3H), 1.77-1.69 (m, 1H),1.28 (d, J=6.0 Hz, 3H). Compound 329: (37.4 mg, 0.090 mmol) as a yellowsolid. Retention time: 6.054 min (Repaired Chiral IC. 0.46*10 cm; 5 μm;MtBE(0.1% DEA):IPA=70:30; 1.0 ml/min); LCMS (ESI) [M+H]⁺=417.2; ¹H NMR(400 MHz, DMSO-d₆) δ 12.77-12.58 (m, 1H), 10.82 (s, 1H), 9.43 (s, 1H),8.51 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 7.65-7.37 (m, 2H),6.94 (d, J=6.1 Hz, 1H), 6.32-6.02 (m, 3H), 2.48-2.30 (s, 2H), 2.22 (s,3H), 1.66 (s, 1H), 1.02 (d, J=6.5 Hz, 3H).

Example 213(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1-carboxamide(Compound 335) and(1R,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1-carboxamide(Compound 334)

Step 1: ethyl (2E)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]prop-2-enoate

A mixture of 4-iodo-1-(triphenylmethyl)-1H-imidazole (7.41 g, 16.98mmol), ethyl (2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate(9.60 g, 42.46 mmol), tetrakis(triphenylphosphine)palladium (1.96 g,1.69 mmol,), potassium phosphate (10.82 g, 50.97 mmol) in 1,4-dioxane(100 mL) and water (20 mL) was stirred for 6 h at 100° C. The reactionwas concentrated under vacuum. The residue was purified by silica gelcolumn with ethyl acetate/petroleum ether (20/80) to afford ethyl(2E)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]prop-2-enoate(2 g, 4.90mmol) as a light yellow solid. LCMS (ESI) [M+H]⁺=409.

Step 2: ethyltrans-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate

A mixture of S,S-dimethylmethanesulfinyl iodide (3.02 g, 13.72 mmol) andt-BuOK (1.54 g, 13.72 mmol) in dimethyl sulphoxide (20 mL) was stirredfor 30 min at 25° C. Ethyl(2E)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]prop-2-enoate (1.4 g, 3.42mmol) was added. The resulting solution was stirring for 15 h at 25° C.The resulting mixture was diluted with water and then extracted withethyl acetate. The organic layers combined and dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum. The residue was purified by silica gel column withdichloromethane/methanol (20/1) to afford ethyltrans-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(360 mg, 0.85 mmol) as yellow oil. LCMS (ESI) [M+H]⁺=423.

Step 3:Trans-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid

A mixture of ethyltrans-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylate(600 mg, 1.42 mmol) and LiOH (170 mg, 7.09 mmol) in tetrahydrofuran (10mL) and water (10 mL) was stirred for 12 h at room temperature. Thereaction mixture was adjusted to pH 4-5 with hydrogen chloride. Theresulting solution was extracted with dichloromethane and dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to affordtrans-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid(460 mg, 1.17 mmol) as a white solid. LCMS (ESI) [M+H]⁺=395.

Step 4:trans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide

To a solution of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (364 mg,1.26 mmol),trans-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxylicacid (500 mg, 1.26 mmol) in dichloromethane (20 mL) and pyridine (3 mL)was added phosphorus oxychloride (290 mg, 1.89 mmol) at 0° C. Themixture was stirred for 30 min at 0° C. The reaction was concentratedunder vacuum. The residue was purified by silica gel column withdichloromethane/methanol (10/1) to affordtrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide(300mg, 0.45 mmol) as a white solid. LCMS (ESI) [M+H]⁺=664.

Step 5: trans-tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]isoquinolin-8-yl]carbamate

A mixture oftrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane-1-carboxamide(600 mg, 0.90 mmol), tert-butyl carbamate (2.1 g, 17.92 mmol),tris(dibenzylideneacetone)dipalladium (187 mg, 0.18 mmol), BrettPhos(193 mg, 0.36 mmol), and cesium carbonate (1.17 g, 3.59 mmol) in1,4-dioxane (20 mL) was stirred for 5 h at 90° C. After filtration, thefiltrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford trans-tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]isoquinolin-8-yl]carbamate(300mg, 0.40 mmol) as a white solid. LCMS (ESI) [M+H]⁺=745.

Step 6:(1S,2S)-N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-5-yl)cyclopropane-1-carboxamideand(1R,2R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1H-imidazol-5-yl)cyclopropane-1-carboxamide

A solution of trans-tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[2-[1-(triphenylmethyl)-1H-imidazol-4-yl]cyclopropane]amido]isoquinolin-8-yl]carbamate(200 mg, 0.26 mmol) in trifluoroacetic acid (5 mL) was stirred for 12 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by reverse phase chromatography(acetonitrile 0-50/0.1% sodium bicarbonate in water) to afford theracemic product (40 mg, 0.09 mmol) as a yellow solid. The racemate wasseparated by Chiral-HPLC to afford two isomers:

-   (Cyclopropane stereochemistry for each isomers: imidazole trans to    amide; All absolute stereochemistry arbitrarily assigned) Compound    335: Retention time:3.38 min(CHIRALPAK ID-3, 0.46*10 cm; 3 μm;    MtBE(0.1% DEA):EtOH=70:30; 1 ml/min); LCMS (ESI) [M+H]⁺=403; ¹HNMR    (400 MHz, CD₃OD) δ 9.27(s, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.39 (s,    1H), 8.32 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=4.0 Hz, 1H), 6.98 (d,    J=4.0 Hz, 1H), 6.92 (s, 1H), 2.51-2.46 (m, 1H), 2.29 (s, 3H),    2.19-2.18(m, 1H), 1.57-1.52 (m, 1H), 1.41-1.38 (m, 1H). Compound    334: Retention time:5.68 min(CHIRALPAK ID-3, 0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):EtOH=70:30; 1 ml/min); LCMS (ESI) [M+H]⁺=403; ¹HNMR    (400 MHz, CD₃OD) δ 9.27(s, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.39 (s,    1H), 8.32 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=4.0 Hz, 1H), 6.98 (d,    J=4.0 Hz, 1H), 6.92 (s, 1H), 2.51-2.46 (m, 1H), 2.29 (s, 3H),    2.19-2.18(m, 1H), 1.57-1.52 (m, 1H), 1.41-1.38 (m, 1H)

Example 214(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 340),(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 339),(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 338) and(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 337)

Step 1: 1-(2,2-difluoroethyl)-4-iodo-1H-pyrazole

A mixture of 4-iodo-1H-pyrazole (3 g, 15.47 mmol),2-bromo-1,1-difluoroethane (2.7 g, 18.63 mmol), potassium carbonate (4.3g, 31.11 mmol) in N,N-dimethylformamide (30 mL) was stirred for 12 hoursat room temperature. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (20/80) to afford1-(2,2-difluoroethyl)-4-iodo-1H-pyrazole (3.3 g, 12.74 mmol) ascolorless oil. LCMS (ESI) [M+H]⁺=259.

Step 2: (E)-tert-butyl 3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)acrylate

A mixture of 1-(2,2-difluoroethyl)-4-iodo-1H-pyrazole (3.3 g, 12.79mmol), tert-butyl prop-2-enoate (4.9 g, 38.23 mmol), palladium acetate(430 mg, 1.92 mmol), tri-o-tolyl phopine (778 mg, 2.56 mmol),triethylamine (1.94 g, 19.172 mmol) in N,N-dimethylformamide (30 mL) wasstirred for 12 hours at 120° C. The resulting solution was diluted withethyl acetate and then washed with water. The organic layers combined,dried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(60/40) to afford tert-butyl(2E)-3-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]prop-2-enoate (2.37 g,9.15 mmol) as a light yellow solid. LC/MS (ESI) [M+H]⁺=259.

Step 3: tert-butyl2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxylate

A mixture of tert-butyl(2E)-3-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]prop-2-enoate (2.9 g,11.23 mmol), thylene glycol dimethyl ether (150 mL, 1.55 mol), lithiumdiisopropylamide (19.6 mL, 365.93 mmol and eethyldiphenylsulfaniumtrifluoroborane fluoride (10.2 g, 33.76 mmol) in dichloromethane (20 mL)was stirred for 5 hours at room temperature. The reaction was thenquenched by water. The resulting solution was extracted withdichloromethane, dried with anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (7/3) to afford tert-butyl2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylate(1.9 g, 6.62 mmol) as yellow oil. LCMS (ESI) [M+H]⁺=287

Step 4:2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxylicacid

A mixture of tert-butyl2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylate(1.9 g, 6.64 mmol) in trifluoroacetic acid (10 mL) and dichloromethane(20 mL) was stirred for 3 hours at room temperature. The resultingmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions (C18 silica gel;CH₃CN/H₂O=5%/95% increasing to CH₃CN/H₂O=40%/60% in 30 min) to afford2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylicacid (1.13 g, 4.89 mmol) as purple oil. LCMS (ESI) [M+H]⁺=231.

Step 5:N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide

A mixture of2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylicacid (1.1 g, 4.78 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (1.4 g,4.87 mmol), phosphorus oxychloride (1.5 g, 9.78 mmol), pyridine (5 mL,62.118 mmol) in dichloromethane (50 mL) was stirred for 30 minutes atroom temperature. The reaction was then quenched by water. The resultingsolution was extracted with ethyl acetate, dried with anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (8/2) to affordN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxamide(1.48 g, 2.96 mmol) as a white solid. LCMS (ESI) [M+H]⁺=500.

Step 6:tert-butyl3-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamido)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixtyre ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxamide(1.4 g, 2.80 mmol), tert-butyl carbamate (9.85 g, 84.08 mmol), BrettPhos(302 mg, 0.56 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (581 mg, 0.56mmol), Cesium carbonate (3.66 g, 11.23 mmol) in 1,4-dioxane (120 mL) wasstirred for 3 hours at 90° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol (8/2)to afford tert-butylN-(3-[[2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1.44 g, 2.48 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=581

Step 7:(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide,(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide,(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamideand(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide

A mixture of tert-butylN-(3-[[2-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1.4 g, 2.41 mmol), HCl/dioxane (30 mL, 354.12 mmol) in methanol (10 mL)was stirred for 1 hour at 25° C. The mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC (C18 silica gel;0.5% sodium bicarbonate in water:ACN=37%-45% in 7 min) to afford themixture (550 mg, 1.15 mmol). The mixture was separated by Chiral-HPLC toafford four isomers (Cyclopropane stereochemistry for each isomer:pyrazole trans to amide; methyl relative stereochemistry arbitrarilyassigned; All absolute stereochemistry arbitrarily assigned): Compound340: (46.5 mg, 0.097 mmol) as a yellow solid. Retention time: 1.65 min(Lux 5u Cellulose-3. 4.6*250 mm, 5 μm; MeOH(0.1% DEA); 4.0 ml/min); LCMS(ESI) [M+H]⁺=481.2; ¹H NMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.42 (s,1H), 8.52 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.63 (s, 1H),7.45-7.34 (m, 2H), 6.95 (d, J=6.1 Hz, 1H), 6.50-6.13 (m, 3H), 4.55 (td,J=15.1, 3.8 Hz, 2H), 2.31-2.22 (m, 5H), 1.66-1.51 (m, 1H), 1.28 (d,J=6.2 Hz, 3H). Compound 339: (163.3 mg, 0.34 mmol) as a yellow solid.Retention time: 1.86 min (Lux 5u Cellulose-3. 4.6*250 mm, 5 μm;MeOH(0.1% DEA); 4.0 ml/min); LCMS (ESI) [M+H]⁺=481.3; ¹H NMR (300 MHz,DMSO-d₆) δ 10.77 (s, 1H), 9.43 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.44 (s,1H), 8.32 (s, 1H), 7.64 (s, 1H), 7.46-7.36 (m, 2H), 6.93 (d, J=6.1 Hz,1H), 6.52-6.16 (m, 3H), 4.60 (td, J=15.2, 3.8 Hz, 2H), 2.37-2.30 (m,1H), 2.22(s, 3H), 2.15 (t, J=4.7 Hz, 1H) 1.70-1.55 (m, 1H), 0.96 (d,J=6.3 Hz, 3H). Compound 338: (173.9 mg, 0.36 mmol) as a yellow solid.Retention time: 2.23 min (Lux 5u Cellulose-3. 4.6*250 mm, 5 μm;MeOH(0.1% DEA); 4.0 ml/min); LCMS (ESI) [M+H]⁺=481.3; ¹H NMR (300 MHz,DMSO-d₆) δ 10.77 (s, 1H), 9.43 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.44 (s,1H), 8.32 (s, 1H), 7.64 (s, 1H), 7.46-7.36 (m, 2H), 6.93 (d, J=6.1 Hz,1H), 6.52-6.16 (m, 3H), 4.60 (td, J=15.2, 3.8 Hz, 2H), 2.37-2.30 (m,1H), 2.22 (s, 3H), 2.15 (t, J=4.7 Hz, 1H) 1.69-1.56 (m, 1H), 0.96 (d,J=6.3 Hz, 3H). Compound 337: (66.3 mg, 0.14 mmol) as a yellow solid.Retention time: 2.91 min (Lux 5u Cellulose-3. 4.6*250 mm, 5 μm;MeOH(0.1% DEA); 4.0 ml/min); LCMS (ESI) [M+H]⁺=481.3; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H), 9.42 (s, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.44 (s,1H), 8.35 (s, 1H), 7.63 (s, 1H), 7.45-7.34 (m, 2H), 6.95 (d, J=6.1 Hz,1H), 6.51-6.13 (m, 3H), 4.55 (td, J=15.2, 3.8 Hz, 2H), 2.31-2.15 (m,5H), 1.66-1.52 (m, 1H), 1.28 (d, J=6.2 Hz, 3H).

Example 215(1R,2S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-((dimethylamino)methyl)cyclopropane-1-carboxamide(Compound 342) and(1S,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-((dimethylamino)methyl)cyclopropane-1-carboxamide(Compound 341)

Step1:3-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione

A mixture of 3-oxabicyclo[3.1.0]hexane-2,4-dione (390 mg, 3.48 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (500 mg,1.73 mmol), 4-dimethylaminopyridine (425 mg, 3.47 mmol) in dioxane (10mL) was stirred for 12 h at 120° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gel columnwith dichloromethane/methanol (10/1) to afford3-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione(450mg, 1.18 mmol) as a white solid. LCMS (ESI) [M+H]⁺=382.

Step 2:Cis-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)cyclopropane-1-carboxamide

To a solution of3-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione(450 mg, 1.17 mmol) in IPA (20 mL) and water (2 mL) was added NaBH₄ (224mg, 5.92 mmol). The mixture was stirred for 1 h at room temperature. Theresulting solution was extracted with ethyl acetate and the organiclayers combined and concentrated under vacuum. The residue was purifiedby silica gel column with dichloromethane/methanol (10/1) to affordcis-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)cyclopropane-1-carboxamide(300mg, 0.78 mmol) as a white solid. LCMS (ESI) [M+H]⁺=386.

Step 3:Cis-[2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]cyclopropyl]methylmethanesulfonate

To a solution ofcis-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(hydroxymethyl)cyclopropane-1-carboxamide(300 mg, 0.77 mmol), triethylamine (236 mg, 2.33 mmol) indichloromethane (20 mL) was added methanesulfonyl chloride (177 mg, 1.54mmol) at 0° C. The mixture was then stirred for 1 h at room temperature.The resulting mixture was washed with water. The resulting solution wasconcentrated under vacuum to affordcis-[2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]cyclopropyl]methylmethanesulfonate(300 mg, 0.64 mmol) as a white solid. LCMS (ESI)[M+H]⁺=464.

Step 4:Cis-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[(dimethylamino)methyl]cyclopropane-1-carboxamide

A mixture ofcis-[2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamoyl]cyclopropyl]methylmethanesulfonate (300 mg, 0.64 mmol), dimethylamine (292 mg, 6.47 mmol)in tetrahydrofuran (5 mL) was stirred for 12 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel column with dichloromethane/methanol (3/1) toaffordcis-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[(dimethylamino)methyl]cyclopropane-1-carboxamide(250mg, 0.60 mmol) as a white solid. LCMS (ESI) [M+H]⁺=413.

Step 5: Cis-tert-butylN-(3-[[2-[(dimethylamino)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

The title compound was prepared in a fashion analogous to that describedfor Example 135 (Compound 36) usingcis-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[(dimethylamino)methyl]cyclopropane-1-carboxamide.LCMS (ESI) [M+H]⁺=494.

Step 6:(1R,25)-N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[(dimethylamino)methyl]cyclopropane-1-carboxamideand(1S,2R)—N-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[(dimethylamino)methyl]cyclopropane-1-carboxamide

The title compound (racemic) was prepared in a fashion analogous to thatdescribed for Example 135 (Compound 36) using cis-tert-butylN-(3-[[2-[(dimethylamino)methyl]cyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate.The racemate was separated by Chiral-HPLC to afford two isomers(Cyclopropane stereochemistry for each isomer: dimethylaminomethyl transto amide; Absolute stereochemistry arbitrarily assigned): Compound 342:Retention time:1.44 min(Lux Cellulose-4, 0.46*5 cm; 3 μm; Hex(8mMNH₃):EtOH=50:50; 1 ml/min); LCMS (ESI) [M+H]⁺=394;¹HNMR (400 MHz,CD₃OD) δ 9.31(s, 1H), 8.48 (d, J=4.0 Hz, 1H), 8.41(s, 1H), 8.34 (s, 1H),7.45 (d, J=4.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.05-3.03 (m, 2H), 2.57(s, 6H), 2.31 (s, 3H), 2.21-2.15 (m, 1H), 1.62-1.56 (m, 1H), 1.30-1.25(m, 1H), 1.18-1.10 (m, 1H). Compound 341: Retention time:2.87 min(LuxCellulose-4, 0.46*5 cm; 3 μm; Hex(8mMNH₃):EtOH=50:50; 1 ml/min); LCMS(ESI) [M+H]+=394; ¹HNMR (400 MHz, CD₃OD) δ 9.31(s, 1H), 8.48 (d, J=4.0Hz, 1H), 8.41(s, 1H), 8.34 (s, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.00 (d,J=8.0 Hz, 1H), 3.05-3.03 (m, 2H), 2.57 (s, 6H), 2.31 (s, 3H), 2.21-2.15(m, 1H), 1.62-1.56 (m, 1H), 1.30-1.25 (m, 1H), 1.18-1.10 (m, 1H).

Example 216(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide(Compound 381),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide(Compound 380),(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide(Compound 379) and(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide (Compound382)

Step 1:2-(4-(2-(8-(tert-butoxycarbonylamino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)-3-methylcyclopropyl)-1H-pyrazol-1-yl)ethylmethanesulfonate

A mixuture of tert-butylN-(7-fluoro-3-[[2-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(670 mg, 1.20 mmol), triethylamine (604 mg, 5.97 mmol), methanesulfonylchloride (273 mg, 2.38 mmol) in dichloromethane (10 mL) was stirred for1 hour at room temperature. The resulting solution was diluted withdichloromethane. The resulting mixture was washed with water. Theorganic phase was dried with anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum to afford2-(4-((2-(8-(tert-butoxycarbonylamino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)-3-methylcyclopropyl)-1H-pyrazol-1-yl)ethylmethanesulfonate (800 mg, 1.25 mmol) as a yellow solid. LCMS (ESI)[M+H]⁺=639.

Step 2: tert-butyl7-fluoro-3-(2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of2-(4-(2-(8-(tert-butoxycarbonylamino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)-3-methylcyclopropyl)-1H-pyrazol-1-yl)ethylmethanesulfonate (700 mg, 1.10 mmol), azetidin-3-ol (320 mg, 4.38 mmol),triethylamine (332 mg, 3.28 mmol) in N,N-dimethylformamide (10 mL) wasstirred for 12 hours at 60° C. The resulting solution was diluted withethyl acetate and then washed with water. The organic phase was driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol (4/1)to afford tert-butyl7-fluoro-3-(2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate(180 mg, 0.29 mmol) as a white solid. LCMS (ESI) [M+H]⁺=616.

Step 3:(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide,(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide,(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamideand(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide

A mixture of tert-butylN-(7-fluoro-3-[[2-[1-[2-(3-hydroxyazetidin-1-yl)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(180 mg, 0.29 mmol) in methanol (3 mL) and HCl/dioxane (10 mL, 6 mol/L)was stirred for 2 hours at room temperature. The mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(C18 silica gel; 0.5% NH₄HCO₃ in water: ACN=2%-50% in 8 min) to affordthe mixture. The mixture was separated by Chiral-HPLC to afford fourisomers (Cyclopropane stereochemistry for each isomer: pyrazole trans toamide; methyl relative stereochemistry arbitrarily assigned; AllAbsolute stereochemistry arbitrarily assigned): Compound 381: (11.1 mg,0.022 mmol) as a yellow solid. Retention time: 2.342 min (CHIRALPAKIC-3. 0.46*10 cm; 3 μm; MtBE(0.1% DEA):EtOH=80:20; 1.0 ml/min); LCMS(ESI) [M+H]⁺=516.4; ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 9.42 (s,1H), 8.51 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.54 (s, 1H),7.40 (d, J=5.1 Hz, 1H), 7.24 (s, 1H), 6.95 (d, J=6.1 Hz, 1H), 6.30 (s,2H), 5.24 (d, J=6.6 Hz, 1H), 4.21-4.05 (m, 1H), 4.01-3.83 (m, 2H),3.51-3.38 (m, 2H), 2.78-2.69 (m, 2H), 2.68-2.60 (m, 2H), 2.28-2.19 (m,4H), 2.18-2.09 (m, 1H), 1.67-1.51 (m, 1H), 1.28 (d, J=6.2 Hz, 3H).Compound 380: (11.7 mg, 0.023 mmol) as a yellow solid. Retention time:3.412 min (CHIRALPAK IC-3. 0.46*10 cm; 3 μm;

-   MtBE(0.1% DEA):EtOH=80:20; 1.0 ml/min); LCMS (ESI) [M+H]⁺=516.4; ¹H    NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 9.42 (s, 1H), 8.51 (d, J=5.0    Hz, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=5.0    Hz, 1H), 7.24 (s, 1H), 6.95 (d, J=6.2 Hz, 1H), 6.30 (s, 2H),    5.31-5.11 (m, 1H), 4.19-4.01 (m, 1H), 3.95 (t, J=6.2 Hz, 2H),    3.50-3.39 (m, 2H), 2.76-2.61 (m, 4H), 2.22 (s, 4H), 2.19-2.12 (m,    1H), 1.67-1.51 (m, 1H), 1.28 (d, J=6.2 Hz, 3H). Compound 379: (22.0    mg, 0.043 mmol) as a yellow solid. Retention time: 9.180 min    (CHIRALPAK IE-3. 0.46*10 cm; 3 μm; MtBE(0.1% DEA):EtOH=75:25; 1.0    ml/min); LCMS (ESI) [M+H]⁺=516.4; ¹H NMR (400 MHz, DMSO-d₆) δ 10.76    (s, 1H), 9.44 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.32    (s, 1H), 7.55 (s, 1H), 7.40 (d, J=5.0 Hz, 1H), 7.30 (s, 1H), 6.93    (d, J=6.1 Hz, 1H), 6.31 (s, 2H), 5.23 (d, J=6.6 Hz, 1H), 4.19-4.08    (m, 1H), 4.01 (t, J=6.2 Hz, 2H), 3.49-3.37 (m, 2H), 2.74 (t, J=6.2    Hz, 2H), 2.69-2.61 (m, 2H), 2.37-2.24 (m, 1H), 2.22 (s, 3H), 2.12    (t, J=4.7 Hz, 1H), 1.67-1.53 (m, 1H), 0.96 (d, J=6.3 Hz, 3H).    Compound 382: (18.5 mg, 0.036 mmol) as a yellow solid. Retention    time: 11.776 min (CHIRALPAK 0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):EtOH=75:25; 1.0 ml/min); LCMS (ESI) [M+H]⁺=516.3; ¹H    NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 9.43 (s, 1H), 8.51 (d, J=5.0    Hz, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.55 (s, 1H), 7.40 (d, J=5.1    Hz, 1H), 7.30 (s, 1H), 6.93 (d, J=6.1 Hz, 1H), 6.31 (s, 2H), 5.23    (d, J=6.6 Hz, 1H), 4.19-4.08 (m, 1H), 4.01 (t, J=6.2 Hz, 2H),    3.46-3.37 (m, 2H), 2.75 (t, J=6.2 Hz, 2H), 2.69-2.61 (m, 2H),    2.34-2.27 (m, 1H), 2.22 (s, 3H), 2.12 (t, J=4.7 Hz, 1H), 1.67-1.53    (m, 1H), 0.96 (d, J=6.3 Hz, 3H).

Example 2172-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 230)

Step 1:2-[[8-Chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

To a solution of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (100 mg,0.35 mmol) in 1,4-dioxane (10 mL) was added2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (110mg, 0.45 mmol), Pd₂(dba)₃. CHCl₃ (72 mg, 0.07 mmol), XantPhos (80 mg,0.14 mmol) and cesium carbonate (290 mg, 0.89 mmol). The resultingmixture was stirred for 2 h at 110° C. After filtration, the filtratewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(15/1) to afford2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(45 mg, 29%) as a yellow solid. LCMS (ESI) [M+H]⁺=451.2.

Step 2: Tert-butylN-[7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate

To a mixture of2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(500 mg, 1.11 mmol) in 1,4-dioxane (45 mL) was added tert-butylcarbamate (3.25 g, 27.74 mmol), Pd₂(dba)_(3.)CHCl₃ (175 mg, 0.17 mmol),BrettPhos (125 mg, 0.23 mmol) and cesium carbonate (1.8 g, 5.525 mmol).The resulting mixture was stirred for 2 h at 90° C. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-[7-fluoro-3-([6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(350 mg, 59%) as a yellow solid. LCMS45 (ESI) [M+H]⁺=532.3.

Step 3:2-[[8-Amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butyl N-[7-fluoro-3-([6-methyl-7-oxo-4H,5H, 6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(350 mg, 0.66 mmol) and dichloromethane (5 mL) in trifluoroacetic acid(10 mL) was stirred for 1.5 h at room temperature. The resulting mixturewas concentrated under vacuum. The pH value of the solution was adjustedto 10 with NH₃ in methanol (7 M). The crude product was purifieddirectly by Prep-HPLC (XBridge Prep C18 OBD Column19*15 mm 5 um; 10 mmolNH₄HCO₃ in water: ACN (20%-40% in 8 min)) to afford2-[[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (90 mg, 32%) as a yellow solid.LCMS (ESI) [M+H]⁺=432.3; ¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.11(s, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.74 (s, 1H), 7.39 (d, J=7.2 Hz,1H), 6.78(d, J=7.2 Hz, 1H), 6.13 (s, 2H), 5.98 (s, 1H), 4.97 (s, 2H),3.84-3.81 (m, 2H), 3.05-3.03 (m, 2H), 2.95 (s, 3H), 2.22 (s, 3H).

Example 218N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-azabicyclo[2.1.1]hexane-2-carboxamide(Compound 336)

Step 1: 4-nitrophenyl8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamate

A mixuture of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (500 mg,1.74 mmol), pyridine (1 mL, 12.424 mmol), 4-nitrophenyl chloroformate(1.05 g, 5.21 mmol) in dichloromethane (10 mL) was stirred for 2 hoursat room temperature. The solids were collected by filtration to afford4-nitrophenylN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamate(800 mg, 1.77 mmol) as a white solid. LCMS (ESI) [M+H]⁺=453.

Step 2:N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-aza-bicyclo[21.1]hexane-2-carboxamide

A mixture of 2-azabicyclo[2.1.1]hexane (658 mg, 7.92 mmol), pyridine (2mL), 4-nitrophenylN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]carbamate(500 mg, 1.10 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was stirred for1 hour at 30° C. The resulting solution was diluted with ethyl acetateand then washed with water. The organic phase was dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum. The residue was purified by silica gel column eluting withdichloromethane/methanol (10/1) to affordN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-azabicyclo[2.1.1]hexane-2-carboxamide(400 mg, 1.01 mmol) of as a white solid. LCMS (ESI) [M+H]⁺=397

Step 3: tert-butyl3-(2-aza-bicyclo[2.1.1]hexane-2-carboxamido)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixuture ofN-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-azabicyclo[2.1.1]hexane-2-carboxamide(900 mg, 2.27 mmol), tert-butyl carbamate (7.98 g, 68.12 mmol),BrettPhos (244 mg, 0.46 mmol), Pd₂(dba)₃. CHCl₃ (470 mg, 0.45 mmol) andcesium carbonate (2.96 g, 9.09 mmol) in 1,4-dioxane (100 mL) was stirredfor 3 hours at 90° C. After filtration, the filtrate was concentratedunder vacuum. The residue was purified by silica gel column eluting withdichloromethane/methanol (9/1) to afford tert-butylN-[3-[([2-azabicyclo[2.1.1]hexan-2-yl]carbonyl)amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(110 mg, 0.23 mmol) of as a purple solid. LCMS (ESI) [M+H]⁺=478.

Step 4:N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-aza-bicyclo[2.1.1]hexane-2-carboxamide

A mixture of tert-butylN-[3-[([2-azabicyclo[2.1.1]hexan-2-yl]carbonyl)amino]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(100 mg, 0.21 mmol) in methanol (2 mL) and HCl/dioxane (10 mL, 6 mol/L)was stirred for 3 hours at room temperature. The mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Atlantis HILIC OBD, 19×150 mm 5 um; water (10 mmol/L NH₄HCO₃):CH₃CN=0%-45% B in 14 min) to affordN-[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-azabicyclo[2.1.1]hexane-2-carboxamide(45.9 mg, 0.12 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=378.2; ¹H NMR(300 MHz, DMSO-d₆) δ 9.39 (s, 1H), 9.01 (s, 1H), 8.53 (d, J=5.3 Hz, 1H),8.46 (s, 1H), 8.13 (s, 1H), 7.43 (d, J=4.7 Hz, 1H), 6.88 (d, J=6.4 Hz,1H), 6.26 (s, 2H), 4.65 (d, J=7.0 Hz, 1H), 3.46-3.39 (m, 2H), 2.88 (s,1H), 2.24 (s, 3H), 1.94 (s, 2H), 1.37-1.28 (m, 2H).

Example 219(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 349),(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 348),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 347) and(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 346)

Step 1:2-(4-(2-(8-(tert-butoxycarbonylamino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-ylcarbamoyl)-3-methylcyclopropyl)-1H-pyrazol-1-yl)ethylmethanesulfonate

A mixture of tert-butylN-(7-fluoro-3-[[2-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 0.36 mmol), triethylamine (72 mg, 0.71 mmol), methanesulfonylchloride (61 mg, 0.53 mmol) in dichloromethane (5 mL) was stirred for 30minutes at room temperature. The resulting mixture was diluted withdichloromethane and then washed with water. The organic phase was driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to afford tert-butylN-(7-fluoro-3-[[2-[1-[2-(methanesulfonyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(240 mg, 0.38 mmol) as a yellow solid. LCMS (ESI) [M+I-I]⁺=639.

Step 2: tert-butyl7-fluoro-3-(2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of tert-butylN-(7-fluoro-3-[[2-[1-[2-(methanesulfonyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(600 mg, 0.94 mmol), morpholine (409 mg, 4.70 mmol) and potassiumcarbonate (260 mg, 1.88 mmol) in N,N-dimethylformamide (6 mL) wasstirred for 12 hours at 70° C. The resulting solution was diluted withwater and then extracted with ethyl acetate. The organic phase was driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by silica gel columneluting with dichloromethane/methanol (9/1) to afford tert-butylN-(7-fluoro-3-[[2-methyl-3-[1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(288 mg, 0.46 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=630.

Step 3:(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamide,(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamide,(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamideand(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamide

A mixture of tert-butylN-(7-fluoro-3-[[2-methyl-3-[1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl]cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(280 mg, 0.45 mmol), methanol (4 mL) and HCl/1,4-dioxane (10 mL, 6mol/L) was stirred for 2 hours at room temperature. The mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(C18 silica gel; 0.5% NH₄HCO₃ in water: ACN=30%-58% in 8 min) to affordthe mixture. The mixture was separated by Chiral-HPLC to afford fourisomers (Cyclopropane stereochemistry for isomers: pyrazole trans toamide; methyl relative stereochemistry arbitrarily assigned; Allabsolute stereochemistry arbitrarily assigned): Compound 349: (19.1 mg,0.036 mmol) as a yellow solid. Retention time: 3.550 min (CHIRALPAKIE-3. 0.46*10 cm; 3 μm;

-   MtBE(0.1% DEA):EtOH=50:50; 1.0 ml/min); LCMS (ESI) [M+H]⁺=530.4; ¹H    NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 9.42 (s, 1H), 8.51 (d, J=5.0    Hz, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.59 (s, 1H), 7.40 (d, J=5.0    Hz, 1H), 7.26 (s, 1H), 6.95 (d, J=6.2 Hz, 1H), 6.30 (s, 2H), 4.14    (t, J=6.7 Hz, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.66 (t, J=4.0 Hz, 2H),    2.39 (s, 4H), 2.27-2.14 (m, 5H), 1.64-1.48 (m, 1H), 1.28 (d, J=6.1    Hz, 3H). Compound 348: (29.2 mg, 0.055 mmol) as a yellow solid.    Retention time: 2.801 min (CHIRALPAK IC-3. 0.46*10 cm; 3 μm;-   MtBE(0.1% DEA):EtOH=80:20; 1.0 ml/min); LCMS (ESI) [M+H]⁺=530.4; ¹H    NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.44 (s, 1H), 8.51 (d, J=5.0    Hz, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.59 (s, 1H), 7.40 (d, J=5.1    Hz, 1H), 7.31 (s, 1H), 6.93 (d, J=6.1 Hz, 1H), 6.30 (s, 2H), 4.18    (t, J=6.6 Hz, 2H), 3.55 (t, J=4.6 Hz, 4H), 2.68 (t, J=6.6 Hz, 2H),    2.41-2.36 (m, 4H), 2.35-2.29 (m, 1H), 2.22 (s, 3H), 2.12 (t, J=4.7    Hz, 1H), 1.69-2.51 (m, 1H), 0.96 (d, J=6.3 Hz, 3H). Compound 347:    (16.7 mg, 0.032 mmol) as a yellow solid. Retention time: 3.608 min    (CHIRALPAK IC-3. 0.46*10 cm; 3 μm; MtBE(0.1% DEA):EtOH=80:20; 1.0    ml/min); LCMS (ESI) [M+H]⁺=530.4; ¹H NMR (400 MHz, DMSO-d₆) δ 10.71    (s, 1H), 9.42 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.35    (s, 1H), 7.59 (s, 1H), 7.44-7.37 (m, 1H), 7.26 (d, J=0.8 Hz, 1H),    6.95 (d, J=6.1 Hz, 1H), 6.30 (s, 2H), 4.14 (t, J=6.7 Hz, 2H), 3.56    (t, J=4.6 Hz, 4H), 2.66 (t, J=6.6 Hz, 2H), 2.43-2.36 (m, 4H),    2.27-2.13 (m, 5H), 1.66-1.48 (m, 1H), 1.28 (d, J=6.1 Hz, 3H).    Compound 346: (33.1 mg, 0.063 mmol) as a yellow solid. Retention    time: 6.022 min (CHIRALPAK IE-3. 0.46*10 cm; 3 μm; MtBE(0.1%    DEA):EtOH=50:50; 1.0 ml/min); LCMS (ESI) [M+H]⁺=530.4; ¹NMR (400    MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.43 (s, 1H), 8.51 (d, J=5.0 Hz, 1H),    8.44 (s, 1H), 8.32 (s, 1H), 7.59 (s, 1H), 7.40 (d, J=5.1 Hz, 1H),    7.31 (s, 1H), 6.93 (d, J=6.1 Hz, 1H), 6.31 (s, 2H), 4.19 (t, J=6.6    Hz, 2H), 3.55 (t, J=4.5 Hz, 4H), 2.68 (s, 2H), 2.38 (s, 4H),    2.34-2.28 (m, 1H), 2.22 (s, 3H), 2.12 (t, J=4.7 Hz, 1H), 1.67-1.53    (m, 1H), 0.96 (d, J=6.3 Hz, 3H).

Example 220(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 351),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 353),(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 352) and(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 350)

Step 1: 5-bromo-4-methyl-2-(1,3-oxazol-2-yl)pyridine

To a solution of 2,5-dibromo-4-methylpyridine (584 mg, 2.32 mmol) in1,4-dioxane (15 mL) was added 2-(tributylstannyl)-1,3-oxazole (1.00 g,2.79 mmol) and tetrakis(triphenylphosphine)palladium (268.95 mg, 0.23mmol). The reaction was stirred for 16 hours 90° C. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (1/1) to afford 5-bromo-4-methyl-2-(1,3-oxazol-2-yl)pyridine (470mg, 84%) as a yellow solid. LCMS (ESI) [M+I-I]⁺=439.1.

Step 2:4-methyl-2-(1,3-oxazol-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 5-bromo-4-methyl-2-(1,3-oxazol-2-yl)pyridine (470 mg,1.96 mmol) in 1,4-dioxane (15 mL) was added4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(4.99 g, 19.65 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (143.85 mg,0.19 mmol) and potassium acetate (482.36 mg, 4.91 mmol). The reactionwas stirred for 16 hours at 90° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/4) to afford4-methyl-2-(1,3-oxazol-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(330 mg, 59%) as yellow oil. LCMS (ESI) [M+H]⁺=287.1.

Step 3:N-(8-chloro-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

To a solution ofN-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(380 mg, 0.78 mmol) in 1,4-dioxane (16 mL) was added4-methyl-2-(1,3-oxazol-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(448.66 mg, 1.56 mmol), potassium carbonate (325.06 mg, 2.35 mmol),X-Phos (37.37 mg, 0.07 mmol), XPhos-PdCl-2nd G (59.57 mg, 0.07 mmol) andwater (3.2 mL). The reaction was stirred for 2 h at 90° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (25/1) to affordtrans-N-(8-chloro-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(210 mg, 52%) as orange oil. LCMS (ESI): [M+H]⁺=517.2.

Step 4: tert-butyl(7-fluoro-3-(2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution ofN-(8-chloro-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(210 mg, 0.40 mmol) in 1,4-dioxane (10 mL) was added tert-butylcarbamate (1.19 g, 10.15 mmol), Pd₂(dba)₃. CHCl₃ (63.07 mg, 0.06 mmol),BrettPhos (43.61 mg, 0.08 mmol) and cesium carbonate (661.78 mg, 2.03mmol). The resulting mixture was stirred for 2 h at 90° C. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (25/1) to afford trans-tert-butyl(7-fluoro-3-(2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-8-yl)carbamate(140 mg, 58%) as orange oil. LCMS (ESI) [M+H]⁺=598.3.

Step 5:(1S,2R,3S)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide,(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamideand(1R,2S,3R)—N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide

To a solution of trans-tert-butyl(7-fluoro-3-(2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-8-yl)carbamate(310 mg, 0.51 mmol) in dichloromethane (15 mL) was added trifluoroaceticacid (15 mL). The resulting solution was stirred for 1 h at roomtemperature. The pH value of the solution was adjusted to 8 with ammoniain methanol (7 mol/L). After filtration, the filtrate was concentratedunder vacuum. The residue was purified by Prep-HPLC to afford themixture (120 mg, 46%) as a yellow solid. The mixture was isolated byChiral-HPLC to afford four isomers (Cyclopropane stereochemistry foreach isomer: pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarilyassigned): Compound 351: (5.7 mg, 5%) as a yellow solid. Retention time:2.261 (XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; Water (0.05%NH₃H₂O) and ACN (25.0% ACN up to 50.0% in 7 min); LCMS (ESI)[M+H]⁺=498.3; ¹HNMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.44 (s, 1H),8.58 (s, 1H), 8.40-8.30 (m, 2H), 8.14 (s, 1H), 7.55-7.45 (m, 2H), 7.25(d, J=0.9 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 6.35 (s, 2H), 3.77 (s, 3H),2.33 (s, 3H), 2.22 (dd, J=8.9, 4.8 Hz, 1H), 2.17-2.11 (m, 1H), 1.57 (dt,J=8.9, 6.3 Hz, 1H), 1.28 (d, J=6.1 Hz, 3H). Compound 353: (5.1 mg, 4%)as a yellow solid. Retention time: 2.691 (XBridge Shield RP18 OBDColumn, 5 μm, 19*150 mm; Water (0.05% NH₃H₂O) and ACN (25.0% ACN up to50.0% in 7 min); LCMS (ESI) [M+H]⁺=498.3; ¹HNMR (400 MHz, DMSO-d₆) δ10.73 (s, 1H), 9.44 (s, 1H), 8.58 (s, 1H), 8.40-8.30 (m, 2H), 8.14 (s,1H), 7.58-7.47 (m, 2H), 7.25 (d, J=0.8 Hz, 1H), 7.02 (d, J=6.1 Hz, 1H),6.36 (s, 2H), 3.77 (s, 3H), 2.33 (s, 3H), 2.22 (dd, J=8.9, 4.8 Hz, 1H),2.18-2.09 (m, 1H), 1.57 (dp, J=8.7, 6.2 Hz, 1H), 1.28 (d, J=6.1 Hz, 3H).Compound 352: (26.5 mg, 22%) as a yellow solid; Retention time: 7.975(XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; Water (0.05% NH₃H₂O)and ACN (25.0% ACN up to 50.0% in 7 min); LCMS (ESI) [M+H]⁺=498.3; ¹HNMR(400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 9.45 (s, 1H), 8.58 (s, 1H),8.39-8.30 (m, 2H), 8.14 (s, 1H), 7.58-7.47 (m, 2H), 7.30 (s, 1H), 7.00(d, J=6.1 Hz, 1H), 6.36 (s, 2H), 3.81 (s, 3H), 2.32 (s, 3H), 2.32-2.28(m, 1H), 2.12 (t, J=4.7 Hz, 1H), 1.60 (ddd, J=9.1, 6.4, 4.8 Hz, 1H),0.96 (d, J=6.2 Hz, 3H). Compound 350: (22.9 mg, 19%) as a yellow solid.Retention time: 9.196 (XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm;Water (0.05% NH₃H₂O) and ACN (25.0% ACN up to 50.0% in 7 min); LCMS(ESI) [M+H]⁺=498.3; ¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.45 (s,1H), 8.58 (s, 1H), 8.39-8.31 (m, 2H), 8.14 (s, 1H), 7.59-7.47 (m, 2H),7.30 (s, 1H), 7.00 (d, J=6.1 Hz, 1H), 6.36 (s, 2H), 3.81 (s, 3H), 2.32(s, 3H), 2.30 (d, J=4.6 Hz, 1H), 2.12 (t, J=4.7 Hz, 1H), 1.66-1.54 (m,1H), 0.96 (d, J=6.2 Hz, 3H).

Example 2212′-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8H)-one(Compound 228)

Step 1:8′-[[6-(4-aminopyridin-3-yl)-8-chloro-7-fluoroisoquinolin-3-yl]amino]-3′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-4′-one

A mixture of8′-bromo-3′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-4′-one(200 mg, 0.74 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (225 mg,0.78 mmol), 3rd generation t-BuBrettPhos precatalyst (266 mg, 0.31mmol), t-BuBrettPhos (151 mg, 0.32 mmol), cesium carbonate (1.27 g, 3.89mmol) in 1,4-dioxane (12 mL). The resulting mixture was stirred for 2 hat 120° C. The resulting mixture was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford8′-[[6-(4-aminopyridin-3-yl)-8-chloro-7-fluoroisoquinolin-3-yl]amino]-3′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-4′-one(110 mg, 31%) as a light yellow solid. LCMS (ESI) [M+H]⁺=477.

Step 2: tert-butylN-[7-fluoro-3-([3′-methyl-4′-oxo-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-8′-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate

A mixture of8′-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-3′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-4′-one(110 mg, 0.23 mmol), tert-butyl carbamate (668 mg, 5.70 mmol),Pd₂(dba)₃. CHCl₃ (48 mg, 0.046 mmol), cesium carbonate (375 mg, 1.15mmol), BrettPhos (37 mg, 0.069 mmol) in 1,4-dioxane (5 mL) was stirredfor 12 h at 90° C. The mixture was filtered and the resulting mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford tert-butylN-[7-fluoro-3-([3′-methyl-4′-oxo-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-8′-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(80 mg, 62%) as a light yellow solid. LCMS (ESI) [M+H]⁺=558.

Step 3:8′-[[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-3′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-4′-one

A mixture of tert-butylN-[7-fluoro-3-([3′-methyl-4′-oxo-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-8′-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(60 mg, 0.11 mmol), hydrogen chloride (2 mL) in dichloromethane (2 mL)and methanol (2 mL) was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by Prep-HPLC (Kinetex EVO C18 Column, 30*150, 5 um; Water (10mmol/L NH₄HCO₃) and ACN (10% to 70% in 4.5 min)) to afford8′-[[8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-3′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrazolo[1,5-d][1,4]diazepine]-4′-one(2.9 mg, 6%) as a yellow solid. LCMS (ESI) [M+H]⁺=458; ¹HNMR (400 MHz,DMSO-d₆) δ 9.27 (s, 1H), 9.02 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 8.43 (s,1H), 7.68 (s, 1H), 7.39 (d, J=6.0 Hz, 1H), 6.79 (d, J=6.0 Hz, 1H), 6.11(s, 2H), 5.61 (s, 1H), 5.06 (s, 2H), 3.73 (s, 2H), 2.99 (s, 3H), 2.22(s, 3H), 1.24-1.18 (m, 2H), 0.96-094 (m, 2H).

Example 222(1R,2R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 357),(1S,2S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 358),(1S,2R,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 359) and(1R,2S,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(Compound 360)

Step 1:N-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide

A mixture of 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine (280.6 mg, 0.87mmol), 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylicacid (420 mg, 2.33 mmol), phosphorus oxychloride (298.4 mg, 1.95 mmol),pyridine (5 mL), dichloromethane (15 mL) was stirred for 5 minutes at 0°C. The resulting solution was stirred for 30 minute at room temperature.The reaction was quenched by water. The resulting solution was extractedwith dichloromethanedried, dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by silica gel column eluting with petroleum ether/ethyl acetate(4/6) to afford(1S,3S)—N-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide(1.1 g, 2.27 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=485.

Step 2: tert-butylN-[(tert-butoxy)carbonyl]-N-[5-(8-chloro-7-fluoro-3-[[(1S,2R,3S)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]isoquinolin-6-yl)-4-methylpyridin-3-yl]carbamate

A mixture ofN-(8-chloro-7-fluoro-6-iodoisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(400 mg, 0.83 mmol), tert-butylN-[(tert-butoxy)carbonyl]-N-[4-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]carbamate(720 mg, 1.66 mmol), terakis(triphenylphosphine)palladium (190 mg, 0.16mmol,), potassium phosphate (520 mg, 2.45 mmol) and water (1 mL) in1,4-dioxane (5 mL) was stirred for 6 hours at 100° C. The reaction wascooled to room temperature, filtered and concentrated under vacuum. Theresidue was purified by silica gel column eluting with petroleumether/ethyl acetate (1/9) to afford tert-butylN-[(tert-butoxy)carbonyl]-N-[5-(8-chloro-7-fluoro-3-[[2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]isoquinolin-6-yl)-4-methylpyridin-3-yl]carbamate(545 mg, 0.82 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=665.

Step 3: tert-butylN-[6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)-7-fluoro-3-[[(1S,2R,3S)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]isoquinolin-8-yl]carbamate

A mixture of tert-butylN-[(tert-butoxy)carbonyl]-N-[5-(8-chloro-7-fluoro-3-[[2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]isoquinolin-6-yl)-4-methylpyridin-3-yl]carbamate(1.15 g, 1.73 mmol), tert-butyl carbamate (5.06 g, 43.19 mmol),Pd₂(dba)_(3.)CHCl₃ (356.5 mg, 0.34 mmol), Brettphos (373.8 mg, 0.70mmol) and cesium carbonate (2.25 g, 6.91 mmol) in 1,4-dioxane (30 mL)was stirred for 3 hours at 110° C. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by silica gel columneluting with dichloromethane/methanol (30/1) to afford tert-butylN-[6-(5-[bis[(tert-butoxy)carbonyl]amino]-4-methylpyridin-3-yl)-7-fluoro-3-[[2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane]amido]isoquinolin-8-yl]carbamate(1.0 g, 1.34 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=746.

Step 4:(1R,2R,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide,(1S,2S,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide,(1S,2R,3S)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamideand(1R,2S,3R)—N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide

A mixture ofN-[8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl]-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide(400 mg, 0.90 mmol) in 4M HCl in 1,4-dioxane (50 mL) was stirred for 2hours at room temperature. The mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC (C18 silica gel; 0.5%NH₄HCO₃ in water:ACN=5%-50% in 9 min) to afford the mixture of isomers.The mixture was separated by Chiral-HPLC to afford four isomers(Cyclopropane stereochemistry for isomer: pyrazole trans to amide;methyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned): Compound 357: (11.4 mg, 0.026mmol) as a yellow solid. Retention time: 2.794 min (Lux 3μ Cellulose-3.100*4.6 mm; MeOH(20 mMNH₃); 4.0 ml/min); LCMS (ESI) [M+H]⁺=446.3; ¹H NMR(300 MHz, Methanol-d₄) δ 9.30 (s, 1H), 8.35 (s, 1H), 8.03 (s, 1H), 7.78(s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 6.99 (d, J=6.1 Hz, 1H), 3.86 (s,3H), 2.34 (t, J=5.7 Hz, 1H), 2.23-2.1 (m, 1H), 2.08 (s, 3H), 1.77-1.52(m, 1H), 1.37 (d, J=6.2 Hz, 3H). Compound 358: (101.8 mg, 0.23 mmol) asa yellow solid. Retention time: 3.089 min (Lux 3μ Cellulose-3. 100*4.6mm; MeOH(20 mMNH₃); 4.0 ml/min); LCMS (ESI) [M+H]⁺=446.3; ¹H NMR (400MHz, DMSO-d₆) δ 10.74 (s, 1H), 9.41 (s, 1H), 8.29 (s, 1H), 7.99 (s, 1H),7.66 (s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.85 (d, J=6.1 Hz, 1H), 6.26(s, 2H), 5.26 (s, 2H), 3.81 (s, 3H), 2.33-2.25 (m, 1H), 2.11 (t, J=4.7Hz, 1H), 1.92 (d, J=1.5 Hz, 3H), 1.66-1.53 (m, 1H), 0.96 (d, J=6.3 Hz,3H). Compound 359: (91.3 mg, 0.21 mmol) as a yellow solid. Retentiontime: 2.505 min (CHIRALPAK IC-3. 100*3 mm, 3 μm; MeOH:ACN=1:1(10 mMNH₃);2.0 ml/min); LCMS (ESI) [M+H]⁺=446.3; ¹H NMR (400 MHz, DMSO-d₆) δ 10.74(s, 1H), 9.41 (s, 1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.54(s, 1H), 7.29 (s, 1H), 6.85 (d, J=6.1 Hz, 1H), 6.25 (s, 2H), 5.26 (s,2H), 3.81 (s, 3H), 2.33-2.25 (m, 1H), 2.11 (t, J=4.7 Hz, 1H), 1.92 (d,J=1.6 Hz, 3H), 1.66-1.53 (m, 1H), 0.96 (d, J=6.3 Hz, 3H). Compound 360:(17.2 mg, 0.039 mmol) as a yellow solid. Retention time: 2.084 min(CHIRALPAK IC-3. 100*3 mm, 3 μm; MeOH:ACN=1:1(10 mMNH₃); 2.0 ml/min);LCMS (ESI) [M+H]⁺=446.3; ¹H NMR (300 MHz, Methanol-d₄) δ 9.30 (s, 1H),8.35 (s, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H),6.99 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 2.34 (t, J=5.6 Hz, 1H), 2.21-2.12(m, 1H), 2.08 (d, J=1.5 Hz, 3H), 1.71-1.52 (m, 1H), 1.37 (d, J=6.2 Hz,3H).

Example 223(S)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 361) and(R)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 362)

Step 1:2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of2-bromo-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(250 mg, 0.98 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (282 mg,0.98 mmol), 3rd generation t-BuBrettPhos precatalyst (335 mg, 0.39mmol), t-BuBrettPhos (189 mg, 0.39 mmol), cesium carbonate (1.6 g, 4.91mmol) in 1,4-dioxane (15 mL) was stirred for 2 h at 130° C. The mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(200 mg, 44%) as a light yellow solid. LCMS (ESI) [M+H]⁺=463.

Step 2: tert-butylN-[7-fluoro-3-([6-methyl-4-methylidene-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate

A mixture of2-[[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]amino]-6-methyl-4-methylidene-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one(180 mg, 0.39 mmol), tert-butyl carbamate (1.14 g, 9.73 mmol),Pd₂(dba)₃. CHCl₃ (81 mg, 0.078 mmol), cesium carbonate (636 mg, 1.95mmol), BrettPhos (63 mg, 0.12 mmol) in 1,4-dioxane (5 mL) was stirredfor 3 h at 90° C. After filtration, the filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (10/1) to afford tert-butylN-[7-fluoro-3-([6-methyl-4-methylidene-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(160 mg, 76%) as a light yellow solid. LCMS (ESI) [M+H]⁺=544.

Step 3: tert-butylN-[3-([4,6-dimethyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate

A mixture of tert-butylN-[7-fluoro-3-([6-methyl-4-methylidene-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(140 mg, 0.26 mmol), palladium on carbon (200 mg) in methanol (10 mL)was stirred under hydrorgen for 1 h at room temperature. Afterfiltration, the filtrate was concentrated under vacuum to affordtert-butylN-[3-([4,6-dimethyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(134 mg, 95%) as a light yellow solid. LCMS (ESI) [M+H]⁺=546.

Step 4:(S)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-oneand(R)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

A solution of tert-butylN-[3-([4,6-dimethyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(150 mg, 0.28 mmol), hydrogen chloride (2 mL) in dichloromethane (2 mL)was stirred for 1 h at room temperature. The resulting solution wasconcentrated under vacuum. The crude product was purified by Prep-HPLC[Kinetex EVO C18 Column, 30*150, 5 um; Water (10 MMOL/L NH₄HCO₃) and ACN(25% to 42% in 7 min)] to afford the racemic product (50 mg, 41%) as ayellow solid. The racemic product was purified by Prep-SFC to afford thesingle enantiomers: Compound 362: (5.7 mg, 11%) as a yellow solid.Retention time: 0.867 min, CHIRALCEL OJ-3, 4.6*50 mm, 3 μm;CO₂/methanol=(50%)/(0.1% DEA, 50%); LCMS (ESI) [M+H]⁺=446; ¹HNMR (400MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.09 (s, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.43(s, 1H), 7.72 (s, 1H), 7.39 (d, J=6.0 Hz, 1H), 6.78 (d, J=6.0 Hz, 1H),6.11 (s, 2H), 6.04 (s, 1H), 5.13-4.81 (m, 2H), 3.99-3.51 (m, 2H),3.32-3.35(m, 1H) 2.97 (s, 3H), 2.22 (s, 3H), 1.26 (d, J=7.0 Hz, 3H).Compound 361: (5.8 mg, 12%) as a yellow solid. Retention time: 1.268min, CHIRALCEL OJ-3, 4.6*50 mm, 3 μm; CO_(2/) methanol=(50%)/(0.1% DEA,50%); LCMS (ESI) [M+H]⁺=446. ¹HNMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H),9.09 (s, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.43 (s, 1H), 7.72 (s, 1H), 7.39(d, J=6.0 Hz, 1H), 6.78 (d, J=6.0 Hz, 1H), 6.11 (s, 2H), 6.04 (s, 1H),5.13-4.81 (m, 2H), 3.99-3.51 (m, 2H), 3.32-3.35(m, 1H) 2.97 (s, 3H),2.22 (s, 3H), 1.26 (d, J=7.0 Hz, 3H).

Example 224(1S,2S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide(Compound 363) and(1R,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide(Compound 364)

Step 1: ethyl (2Z)-3-(1H-pyrazol-5-yl)prop-2-enoate

A mixture of ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (3.04g, 9.15 mmol), sodium hydride (400 mg, 16.66 mmol),1H-pyrazole-5-carbaldehyde (800 mg, 8.32 mmol) in tetrahydrofuran (100mL) was stirred for 2 h at room temperature. The reaction was quenchedwith water. The resulting mixture was extracted with ethyl acetate andthe organic layers combined and concentrated under vacuum. The residuewas purified by flash chromatography on a silica gel column eluted withethyl acetate/petroleum ether (1/3) to afford ethyl(2Z)-3-(1H-pyrazol-5-yl)prop-2-enoate (500 mg, 2.99 mmol) as a whitesolid. LCMS (ESI) [M+H]⁺=167.

Step 2: ethyl (2Z)-3-[1-(oxan-2-yl)-1H-pyrazol-5-yl]prop-2-enoate

A mixture of ethyl (2Z)-3-(1H-pyrazol-5-yl)prop-2-enoate (530 mg, 3.18mmol), 3,4-dihydro-2H-pyran (536 mg, 6.37 mmol), TsOH (27 mg, 0.15 mmol)in ethyl acetate (20 mL) was stirred for 2 h at 80° C. The resultingmixture was concentrated under vacuum. The residue was purified by flashchromatography on a silica gel column eluted with ethylacetate/petroleum ether (1/10) to afford ethyl(2Z)-3-[1-(oxan-2-yl)-1H-pyrazol-5-yl]prop-2-enoate (600 mg, 2.39 mmol)as colorless oil. LCMS (ESI) [M+H]⁺=251

Step 3: ethyltrans-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxylate

A mixture of trimethyl(oxo)-1̂[6]-sulfanylium iodide (3.52 g, 15.99mmol), t-BuOK (1.792 g, 15.97 mmol), ethyl(2Z)-3-[1-(oxan-2-yl)-1H-pyrazol-5-yl]prop-2-enoate (2 g, 7.99 mmol) inDMSO (20 mL) was stirred for 2 h at room temperature. The resultingsolution was diluted with water. The resulting solution was extractedwith ethyl acetate and the organic layers combined and concentratedunder vacuum. The residue was purified by flash chromatography on asilica gel column eluted with ethyl acetate/petroleum ether (1/10) toafford trans ethyl-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxylate (400 mg,1.52 mmol) as colorless oil. LCMS (ESI) [M+H]⁺=265

Step 4: trans-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxylicacid

A mixture of trans ethyl-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxylate (400 mg,1.51 mmol), lithium hydroxide (180 mg, 7.51 mmol) in tetrahydrofuran (10mL) and water (10 mL) was stirred for 5 h at room temperature. Thereaction mixture was adjusted to pH 4 with hydrogen chloride. Theresulting solution was extracted with ethyl acetate and the organiclayers combined and concentrated under vacuum to affordtrans-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxylic acid(300 mg, 1.27 mmol) as a white solid. LCMS (ESI) [M+H]⁺=237.

Step 5:trans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxamide

A mixture oftrans-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxylic acid(350 mg, 1.48 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (426 mg,1.48 mmol) in Pyridine (1 mL) and dichloromethane (10 mL) was addedphosphorus oxychloride (450 mg, 2.93 mmol). The resulting solution wasstirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on a silica gel column eluted withdichloromethane/methanol (95/5) to affordtrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxamide(300 mg, 0.59 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=506

Step 5: trans-tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane]amido]isoquinolin-8-yl]carbamate

A mixture of tert-butyl carbamate (1.67 g, 14.25 mmol),trans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane-1-carboxamide(360 mg, 0.71 mmol), Pd₂(dba)_(3.)CHCl₃ (150 mg, 0.14 mmol), BrettPhos(153 mg, 0.28 mmol), cesium carbonate (930 mg, 2.85 mmol) in dioxane (10mL) was stirred for 12 h at 90° C. under nitrogen. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (10/1) to afford trans-tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane]amido]isoquinolin-8-yl]carbamate(200 mg, 0.34 mmol) as a white solid. LCMS (ESI) [M+H]⁺=587

Step 6:(1S,2S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)cyclopropane-1-carboxamideand(1R,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide

A mixture of trans-tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[[-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]cyclopropane]amido]isoquinolin-8-yl]carbamate(200 mg, 0.34 mmol) in trifluoroacetic acid (5 mL) was stirred for 1 hat room temperature.The resulting mixture was concentrated under vacuum.The residue was purified by reverse phase chromatography (acetonitrile0-50/0.1% NH₄HCO₃ in water) to afford the racemic product (70 mg, 0.17mmol) as a white solid. The racemate product was separated byChiral-HPLC to afford two isomers (Cyclopropane stereochemistry:pyrazole trans to amide): Compound 364: Retention time:1.69 min (LuxCellulose-4, 0.46*5 cm; 3 μm; Hex(0.1% DEA):EtOH=50:50; 1 ml/min); LCMS(ESI) [M+H]⁺=402; ¹HNMR (400 MHz, CD₃OD) δ 9.29 (s, 1H), 8.47 (d, J=5.2Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 7.58-7.56 (m, 1H), 7.44 (d, J=5.2Hz, 1H), 7.00(d, J=6 Hz, 1H), 6.18-6.16 (m, 1H), 2.60-2.59 (m, 1H), 2.31(s, 3H), 2.29-2.25 (m, 1H), 1.64-1.61 (m, 1H), 1.44-1.42 (m, 1H);Compound 363: Retention time: 3.07 min (Lux Cellulose-4, 0.46*5 cm; 3μm; Hex(0.1% DEA):EtOH=50:50; 1 ml/min); LCMS (ESI) [M+H]⁺=402; ¹HNMR(400 MHz, CD₃OD) δ 9.29 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.42 (s, 1H),8.35 (s, 1H), 7.58-7.56(m, 1H), 7.44 (d, J=5.2 Hz, 1H), 7.00(d, J=6 Hz,1H), 6.18-6.16 (m, 1H), 2.60-2.59 (m, 1H), 2.31 (s, 3H), 2.29-2.25 (m,1H), 1.64-1.61 (m, 1H), 1.44-1.42 (m, 1H).

Example 225(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 368),(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 367),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 366) and(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide(Compound 365)

Step 1: 1-(2-(benzyloxy)ethyl)-4-iodo-1H-pyrazole

A mixture of 4-iodo-1H-pyrazole (10 g, 51.55 mmol),(2-bromoethoxy)methyl]benzene (13.24 g, 61.54 mmol), potassium carbonate(14.23 g, 102.94 mmol) in N,N-dimethylformamide (25 mL) was stirred for2 hours at room temperature. The resulting solution was diluted withethyl acetate. The resulting mixture was washed with water. The organicphase was dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The residue was purified bysilica gel column eluting with ethyl acetate/petroleum ether (1/1) toafford 1-[2-(benzyloxy)ethyl]-4-iodo-1H-pyrazole (20 g, 60.79 mmol) asyellow oil. LCMS (ESI) [M+H]⁺=329.

Step 2: (E)-tert-butyl3-(1-(2-(benzyloxy)ethyl)-1H-pyrazol-4-yl)acrylate

A mixture of 1-[2-(benzyloxy)ethyl]-4-iodo-1H-pyrazole (22 g, 67.04mmol), tert-butyl prop-2-enoate (25.76 g, 200.95 mmol), palladiumacetate (2.25 g, 10.04 mmol), tri-o-tolyl phopine (12.23 g, 40.18 mmol)and triethylamine (10.16 g, 100.43 mmol) in N,N-dimethylformamide (150mL) was stirred for 12 hours at 110° C. The resulting solution wasdiluted with ethyl acetate and then washed with water and concentrated.The residue was purified by silica gel column eluting with ethylacetate/petroleum ether (4/6) to afford tert-butyl(2E)-3-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]prop-2-enoate (13.8 g,41.95 mmol) as yellow oil. LCMS (ESI) [M+H]⁺=329.

Step 3: (1S,2S)-tert-butyl2-(1-(2-(benzyloxy)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxylate

LDA (19 mL, 45.67 mmol) was added to a mixture of tert-butyl(2E)-3-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]prop-2-enoate (5 g, 15.23mmol) and ethylene glycol dimethyl ether (100 mL) at −78° C. Thesolution was stirred for 1 hour at this temperature. Thenethyldiphenylsulfanium trifluoroborane fluoride (13.8 g, 45.67 mmol) wasadded at −78° C. and then stirred for 5 hours at room temperature. Thereaction was then quenched by the addition water. The resulting mixturewas extracted with dichloromethane. The organic layers were dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by silica gel columneluting with ethyl acetate/petroleum ether (7/3) to afford tert-butyl2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylate(4 g, 11.20 mmol) as red oil. LCMS (ESI) [M+H]⁺=357.

Step 4:2-(1-(2-(benzyloxy)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxylicacid

A mixture of tert-butyl2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylate(3.9 g, 10.94 mmol), trifluoroacetic acid (10 mL) in dichloromethane (50mL). The resulting solution was stirred for 3 hours at room temperature.The resulting mixture was concentrated under vacuum to afford2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylicacid (5 g, crude) as purple oil. LCMS (ESI) [M+H]⁺=301.

Step 5:2-(1-(2-(benzyloxy)ethyl)-1H-pyrazol-4-yl)-N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-methylcyclopropanecarboxamide

A mixture of2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane-1-carboxylicacid (5.6 g, 18.65 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (5.36 g,18.62 mmol), pyridine (20 mL) and phosphorus oxychloride (5.71 g, 37.25mmol) in dichloromethane (100 mL, 1.57 mol) was stirred for 30 minutesat room temperature. The reaction was then quenched by water. Theresulting solution was extracted with dichloromethane. The organiclayers were dried with anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under vacuum. The residue was purified bysilica gel column eluting with ethyl acetate/petroleum ether (7/3) toafford2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(6.1 g, 10.70 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=570.

Step 6: tert-butyl3-((1S,2S)-2-(1-(2-(benzyloxy)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamido)-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(6.1 g, 10.70 mmol), tert-butyl carbamate (37.63 g, 321.21 mmol),Pd₂(dba)₃. CHCl₃ (2.22 g, 2.14 mmol), BrettPhos (1.15 g, 2.14 mmol) andcesium carbonate (13.98 g, 42.91 mmol) in 1,4-dioxane (100 mL) wasstirred for 5 hours at 90° C. The solids were filtered out. The residuewas purified by silica gel column eluting with dichloromethane/methanol(4/1) to tert-butylN-(3-[[2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(6.8 g, 10.45 mmol) as a purple solid. LCMS (ESI) [M+H]⁺=651.

Step 7: tert-butyl7-fluoro-3-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate

A mixture of tert-butylN-(3-[[(1S,2S)-2-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(1.5 g, 2.31 mmol), Pd(OH)₂/C (646 mg, 4.60 mmol) and methanol (50 mL)was bubbled through with hydrogen gas for 20 min. The resulting solutionwas stirred for 12 hours under hydrogen (balloon) at 50° C. The mixturewas filtered and concentrated. The residue was purified by silica gelcolumn eluting with dichloromethane/methanol (96/4) to afford tert-butylN-(7-fluoro-3-[[2-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(250 mg, 0.45 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=561.

Step 8:(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide,(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide,(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamideand(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropanecarboxamide

A mixture of tert-butylN-(7-fluoro-3-[[2-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 0.36 mmol) in HCl/1,4-dioxane (10 mL) was stirred for 1 hour atroom temperature. The mixture was concentrated under vacuum. The crudeproduct was purified by Prep-HPLC (C18 silica gel; 0.5% NH₄HCO₃ inwater: ACN=20%-50% in 7 min) to afford the mixture of 4 isomers. Themixture was separated by Chiral-HPLC to afford four isomers(Cyclopropane stereochemistry for each isomer: pyrazole trans to amide;methyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned): Compound 368: (12.1 mg, 0.026mmol) as a yellow solid. Retention time: 4.112 min (Chiral IA.0.46*15cm; 5 μm; MeOH(0.1% DEA): dichloromethane=80:20; 1.0 ml/min); LCMS (ESI)[M+H]⁺=461.3; ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.42 (s, 1H),8.52 (d, J=5.0 Hz, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.55 (s, 1H), 7.41(d, J=5.1 Hz, 1H), 7.27 (d, J=0.8 Hz, 1H), 6.95 (d, J=6.1 Hz, 1H), 6.31(s, 2H), 4.87 (s, 1H), 4.06 (t, J=5.7 Hz, 2H), 3.69 (t, J=5.7 Hz, 2H),2.22 (s, 3H), 2.28-2.13 (m, 2H), 1.62-1.49 (m, 1H), 1.28 (d, J=6.2 Hz,3H).Compound 367: (20.5 mg, 0.045 mmol) as a yellow solid. Retentiontime: 2.172 min (Lux Cellulose-4. 0.46*5 cm; 3 μm;Hex(8mMNH₃):EtOH=60:40; 1.0 ml/min); LCMS (ESI) [M+H]⁺=461.3; ¹H NMR(400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.43 (s, 1H), 8.51 (d, J=5.0 Hz,1H), 8.43 (s, 1H), 8.32 (s, 1H), 7.57 (s, 1H), 7.40 (d, J=5.1 Hz, 1H),7.32 (s, 1H), 6.93 (d, J=6.1 Hz, 1H), 6.30 (s, 2H), 4.89 (t, J=5.3 Hz,1H), 4.10 (t, J=5.7 Hz, 2H), 3.80-3.63 (m, 2H), 2.33-2.27 (m, 1H), 2.22(s, 3H), 2.13 (t, J=4.7 Hz, 1H), 1.67-1.54 (m, 1H), 0.97 (d, J=6.3 Hz,3H). Compound 366: (10.2 mg, 0.022 mmol) as a yellow solid. Retentiontime: 3.118 min (Lux Cellulose-4. 0.46*5 cm; 3 μm; Hex(8mMNH₃):EtOH=60:40; 1.0 ml/min); LCMS (ESI) [M+H]⁺=461.3; ¹H NMR (400MHz, DMSO-d₆) δ 10.71 (s, 1H), 9.42 (s, 1H), 8.51 (d, J=5.0 Hz, 1H),8.44 (s, 1H), 8.35 (s, 1H), 7.55 (s, 1H), 7.40 (d, J=5.0 Hz, 1H), 7.27(s, 1H), 6.95 (d, J=6.1 Hz, 1H), 6.30 (s, 2H), 4.86 (t, J=5.3 Hz, 1H),4.06 (t, J=5.7 Hz, 2H), 3.80-3.59 (m, 2H), 2.22 (s, 3H), 2.28-2.13 (m,2H), 1.62-1.50 (m, 1H), 1.28 (d, J=6.2 Hz, 3H). Compound 365: (25.4 mg,0.055 mmol) as a yellow solid. Retention time: 7.392 min (Chiral IA.0.46*15 cm; 5 μm; MeOH(0.1% DEA):dichloromethane=80:20; 1.0 ml/min);LCMS (ESI) [M+H]⁺=461.2; ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.43(s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 7.57 (s,1H), 7.43 (d, J=5.1 Hz, 1H), 7.32 (s, 1H), 6.93 (d, J=6.1 Hz, 1H), 6.31(s, 2H), 4.89 (s, 1H), 4.10 (t, J=5.7 Hz, 2H), 3.71 (t, J=5.7 Hz, 2H),2.39-2.30 (m, 1H), 2.23 (s, 3H), 2.13 (t, J=4.7 Hz, 1H), 1.67-1.54 (m,1H), 0.97 (d, J=6.2 Hz, 3H).

Example 226(1R,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(Compound 356) and(1S,2S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(Compound 355)

Step 1: tert-butyl (2E)-3-(1-methyl-1H-1,2,3-triazol-4-yl)prop-2-enoate

A solution of 4-bromo-1-methyl-1H-1,2,3-triazole (5 g, 30.87 mmol),tert-butyl prop-2-enoate (11.9 g, 92.85 mmol), palladium acetate (1.1 g,4.90 mmol), tri-o-tolylphosphane (1.9 g, 6.24 mmol) and triethylamine(4.7 g, 46.45 mmol) in N,N-dimethylformamide (50 mL, 646.09 mmol) wasstirred for 12 h at 110° C. The resulting mixture was cooled to roomtemperature and then diluted with water. The resulting solution wasextracted with ethyl acetate, dried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on a silica eluted with ethylacetate/petroleum ether (3/2) to afford tert-butyl(2E)-3-(1-methyl-1H-1,2,3-triazol-4-yl)prop-2-enoate (3.6 g, 17.23 mmol)as a yellow solid. LCMS (ESI) [M+H]⁺=210.

Step 2:trans-tert-butyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylate

To a solution of trimethyl(oxo)-[6]-sulfanylium iodide (7.6 g, 34.53mmol) and potassium tert-butoxide (3.9 g, 34.76 mmol) in dimethylsulphoxide (80 mL) was added tert-butyl(2E)-3-(1-methyl-1H-1,2,3-triazol-4-yl)prop-2-enoate (3.6 g, 17.21 mmol)at room temperature for 12 hours. The resulting solution was dilutedwith water. The resulting solution was extracted with ethyl acetate,dried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum to affordtrans-tert-butyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylate(1.3 g, crude) as a yellow oil. LCMS (ESI) [M+H]⁺=224.

Step 3:trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylic acid

To a solution oftrans-tert-butyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylate(1.3 g, 5.82 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (2 mL, 26.93 mmol) at room temperature for 2 hours. The resultingmixture was concentrated under vacuum, the residue was purified by areversed-phase column chromatography (0.5% NH₄HCO₃ in water/CH₃CN=5%-50%in 25 min) to affordtrans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylic acid(223 mg, 1.34 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=168.

Step 4:trans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide

To a solution oftrans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylic acid(223 mg, 1.33 mmol),8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (320 mg,1.11 mmol) and pyridine (0.5 mL, 6.21 mmol) in dichloromethane (5 mL,78.65 mmol) was added phosphorus oxychloride (258 mg, 1.68 mmol) at 0°C. The resulting solution was stirred at room temperature for 30 min.The reaction was quenched by water and then extracted withdichloromethane .The organic layers was dried over with anhydrous sodiumsulfate, filtered and concentrated under vacuum to affordtrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(262 mg, 0.60 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=437.

Step 5: trans-tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture oftrans-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(242 mg, 0.55 mmol), tert-butyl carbamate (1.95 g, 16.65 mmol),tris(dibenzylideneacetone)dipalladium (115 mg, 0.11 mmol), Brettphos (60mg, 0.11 mmol) and cesium carbonate (724 mg, 2.22 mmol) in 1,4-dioxane(12 mL) was stirred at 100° C. for 2 h. After filtration, the filtratewas concentrated under vacuum. The residue was purified by flashchromatography on silica eluted with dichloromethane/methanol (92/8) toafford trans-tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(120mg, 0.23 mmol) as a red solid. LCMS (ESI) [M+H]⁺=518.

Step 6:(1R,2R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamideand(1S,2S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide

A solution of trans-tert-butylN-(7-fluoro-3-[[2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(100 mg, 0.19 mmol) in 1,4-dioxane (2.5 mL, 29.510 mmol) and hydrogenchloride (2.5 mL, 82.280 mmol) was stirred at room temperature for 3 h.After concentrated under vacuum the residue was purified by Prep-HPLC(XBridge Prep C18 OBD 19*150 mm*5 um; 10 mmol NH₄HCO₃ in water:CH₃CN=10%-50% in 7 min) to afford the racemic product. The racemicproduct was separated by Prep-Chiral-HPLC to afford two isomers(Cyclopropane stereochemistry the two isomers: triazole trans to amide,All absolute stereochemistry arbitrarily assigned): Compound 355: (8.7mg, 0.021 mmol) as a yellow solid. Retention time; 1.977 mins((CHIRALPAK IC2*25 cm, 5 μm; MeOH(0.1% DEA):DICHLOROMETHANE=70:30); LCMS(ESI) [M+H]⁺=418; ¹HNMR(400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.43 (s, 1H),8.52 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 7.93 (s, 1H),7.44-7.37 (m, 1H), 6.94 (d, J=6.1 Hz, 1H), 6.32 (s, 2H), 4.00 (s, 3H),2.49-2.40 (m, 2H), 2.22 (s, 3H), 1.50-1.35 (m, 2H). Compound 356: (10.3mg, 0.025 mmol) as a yellow solid. Retention time: 2.424 mins,((CHIRALPAK IC2*25 cm, 5 μm; MeOH(0.1% DEA):DICHLOROMETHANE=70:30); LCMS(ESI) [M+H]⁺=418; ¹HNMR(400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.43 (s, 1H),8.52 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 7.93 (s, 1H),7.44-7.37 (m, 1H), 6.94 (d, J=6.1 Hz, 1H), 6.32 (s, 2H), 4.00 (s, 3H),2.49-2.40 (m, 2H), 2.22 (s, 3H), 1.50-1.35 (m, 2H).

Example 227(±)-(1S,2R,6R,7S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(Compound 373 and Compound 374) and(±)-(1S,2S,6R,7S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(racemic) (Compound 371 and Compound 372)

Step 1: exo-ethyl 2-oxobicyclo[4.1.0]heptane-7-carboxylate

A mixture of cyclohex-2-en-1-one (4 g, 41.61 mmol), Ru₂(OAc)₄ (0.91 g,2.05 mmol) in dichloromethane (40 mL) was added dropwised ethyl2-(lambda4,-diazynyl)acetate (7.86 g, 68.28 mmol) at 0° C. The reactionwas stirred for 2 h at 25° C. The reaction was then quenched with water,extracted with dichloromethane. The organic layers dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1:4) to afford exo-ethyl2-oxobicyclo[4.1.0]heptane-7-carboxylate was abtained (2 g, 0.011 mol)as yellow oil. LCMS (ESI) [M+H]⁺=183.2.

Step 2: exo-2-oxobicyclo[4.1.0]heptane-7-carboxylic acid

To a mixture of exo-ethyl 2-oxobicyclo[4.1.0]heptane-7-carboxylate (2 g,10.97 mmol) in tetrahydrofuran (20 mL) was added LiOH (1.05 g, 43.84mmol) in water (5 mL) was stirred for 3 h at 25° C. The pH value of thesolution was adjusted to 5 with citric acid and then extracted withdichloromethane.The organic layers dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum to offordexo-2-oxobicyclo[4.1.0]heptane-7-carboxylic acid (1.26 g, 74%) as abrown solid. LCMS (ESI) [M+H]⁺=155.2.

Step 3:exo-N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-oxobicyclo[4.1.0]heptane-7-carboxamide

To a solution of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (2.2 g,7.64 mmol), exo-2-oxobicyclo[4.1.0]heptane-7-carboxylic acid (1.18 g,7.654 mmol), pyridine (12 mL, 206.32 mmol) in dichloromethane (68 mL)was added dropwise phosphorus oxychloride (2.36 g, 15.39 mmol) at 5° C.The reaction was stirred for 30 min at 5° C. The reaction was thenquenched with water, extracted with dichloromethane. The organic layersdried with anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to affordexo-N-(8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-oxobicyclo[4.1.0]heptane-7-carboxamide(2.5 g, 77%) as a yellow solid. LCMS (ESI) [M+H]⁺=424.2.

Step 4: exo-tert-butyl(7-fluoro-6-(4-methylpyridin-3-yl)-3-(2-oxobicyclo[4.1.0]heptane-7-carboxamido)isoquinolin-8-yl)carbamate

A mixture ofexo-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-oxobicyclo[4.1.0]heptane-7-carboxamide(1.1 g, 2.59 mmol), tert-butyl carbamate (7.6 g, 64.87 mmol), Pd₂(dba)₃.CHCl₃ (540 mg, 0.52 mmol), Brettphos (560 mg, 1.04 mmol), cesiumcarbonate (3.4 g, 10.43 mmol,) in 1,4-dioxane (40 mL) was stirred for 2h at 90° C. The mixture was filtered and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford tert-butyl7-fluoro-6-(4-methylpyridin-3-yl)-3-(2-oxobicyclo[4.1.0]heptane-7-carboxamido)isoquinolin-8-ylcarbamate(800 mg, 1.59 mmol) as a brown solid. LCMS (ESI) [M+H]⁺=505.3.

Step 5: exo-tert-butyl(7-fluoro-3-(2-hydroxybicyclo[4.1.0]heptane-7-carboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture of tert-butylN-[7-fluoro-6-(4-methylpyridin-3-yl)-3-[(7S)-2-oxobicyclo[4.1.0]heptane-7-amido]isoquinolin-8-yl]carbamate(800 mg, 1.58 mmol) and NaBH₄ (362 mg, 9.56 mmol) in methanol (20 mL)was stirred for 90 min at 0° C. The reaction was then quenched by water,extracted with dichloromethane. The organic layers were dried withanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford exo-tert-butyl7-fluoro-3-(2-hydroxybicyclo[4.1.0]heptane-7-carboxamido)-6-(4-methylpyridin-3-yl)isoquinolin-8-ylcarbamate(370 mg, 46%) as a yellow solid.

Step 6:(1S,2R,6R,7S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(racemic) and(1S,2S,6R,7S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(racemic)

A solution of exo-tert-butylN-[7-fluoro-3-(2-hydroxybicyclo[4.1.0]heptane-7-amido)-6-(4-methylpyridin-3-yl)isoquinolin-8-yl]carbamate(200 mg, 0.39 mmol) in N,N-dimethylformamide (1 mL) was added HCl(g)/dioxane(10 mL, 4 M). The reaction was stirred for 2 h at 20° C. Theresulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford two isomers. The mixtures werefurther separated on chiral HPLC to afford 4 singler stereoisomers. Therelative stereochemistry is as drawn in Table 1; but the absolutestereochemistry has been assigned arbitrarily). Compound 371: Retentiontime; 2.74 mins ((CHIRALPAK OJ-3 4.6×50 mm; MeOH(0.1% DEA); LCMS (ESI)[M+H]⁺=407. Compound 372: Retention time; 1.56 mins ((CHIRALPAK OJ-34.6×50 mm; MeOH(0.1% DEA); LCMS (ESI) [M+H]⁺=407. Compound 373:Retention time; 1.25 mins ((Cellulose-4, 4.6×50 mm; MeOH(0.1% DEA); LCMS(ESI) [M+H]⁺=407. Compound 374: Retention time; 3.03 mins ((ChiralcelOJ-3, 4.6×50 mm; MeOH(0.1% DEA); LCMS (ESI) [M+H]⁺=407.

Example 228(±)-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 192) and(±)-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 191)

Step 1: tert-butylN-(3-[[2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

A mixture of2-[(benzyloxy)methyl]-N-[8-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(420 mg, 0.89 mmol), tert-butyl carbamate (2.61 g 22.2 mmol), Pd₂(dba)₃.CHCl₃ (184 mg, 0.178 mmol), Brettphos (191 mg, 0.36 mmol), cesiumcarbonate (1.16 g, 3.566 mmol) in dioxane (10 mL, 118.041 mmol) wasstirred for 1.5 h at 120° C. The resulting mixture was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (4/1) to affordtert-butylN-(3-[[2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(450 mg, 92%) as a yellow solid. LCMS (ESI) [M+H]⁺=472.2.

Step 2: tert-butylN-(3-[[2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of tert-butylN-(3-[[(1S,2S)-2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(350 mg, 0.63 mmol) in methanol (30 mL) was added Pd(OH)₂/C (2.5 g,17.80 mmol). The resulting solution was stirred under hydrogen for 30min at 25° C. After filtration, the resulting mixture was concentratedunder vacuum to afford tert-butylN-(3-[2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 68%) as a light green solid. LCMS (ESI) [M+H]⁺=463.3

Step 3:(2-((8-((tert-butoxycarbonyl)amino)-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)carbamoyl)-3-methylcyclopropyl)methylmethanesulfonate

To a solution of tert-butylN-(3-[[2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(140 mg, 0.30 mmol), triethylamine (183 mg, 1.81 mmol) indichloromethane (3 mL, 47.19 mmol) was dropwised MSCl (138 mg, 1.21mmol). The resulting solution was stirred for 30 min at 25° C. Thereaction was then quenched by water. The resulting mixture was extractedwith dichloromethanedried with anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under vacuum to afford((1S,2S)-2-[8-((tert-butoxycarbonyl)amino)-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)carbamoyl)-3-methylcyclopropyl)methylmethanesulfonate (100 mg, 0.19 mmol) as yellow oil. LCMS (ESI)[M+H]⁺=541.3.

Step 4: tert-butylN-(3-[[(1S,2S)-2-(cyanomethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of tert-butylN-(3-[[2-(methanesulfonylmethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(100 mg, 0.19 mmol) in DMSO (3 mL, 42.24 mmol) was added KCN (99.29 mg,1.53 mmol). The resulting solution was stirred for 2 h at 50° C. Theresulting solution was diluted with water. The resulting solution wasextracted with dichloromethane dried with anhydrous sodium sulfate.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford tert-butylN-(3-[[(1S,2S)-2-(cyanomethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(70 mg, 78%) as a brown solid. LCMS (ESI) [M+H]⁺=472.3

Step 5:(±)-(1S,2S)—N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamideand(±)-(1S,2S)—N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide

To a solution of tert-butylN-(3-[[2-(cyanomethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(70 mg, 0.15 mmol) in dichloromethane (1 mL, 15.73 mmol) andtrifluoroacetic acid (1 mL) was stirred for 30 min at 25° C. Theresulting solution was concentrated under vacuum. The crude product waspurified by Prep-HPLC (XBridge Prep Amide OBD Column, 19×150 mm 5 um;water (0.05% NH₃H₂O): ACN (20%-55% in 6 min) to afford two pairs ofenantiomers (Cyclopropane stereochemistry: cyanomethyl trans to amide;All absolute stereochemistry arbitrarily assigned): Compound 191: as ayellow solid (2.8 mg, 5%). LCMS (ESI) [M+H]⁺=372.2.; ¹HNMR (400 MHz,DMSO-d₆) δ 10.80 (s, 1H), 9.32 (s, 1H), 8.67-8.39 (m, 2H), 8.26 (s, 1H),7.45 (d, J=5.1 Hz, 1H), 6.81 (s, 1H), 6.55 (d, J=1.5 Hz, 1H), 6.37 (s,2H), 2.81 (dd, J=17.6, 7.3 Hz, 1H), 2.69 (dd, J=17.7, 7.7 Hz, 1H), 2.33(s, 3H), 1.79 (t, J=4.5 Hz, 1H), 1.71-1.57 (m, 1H), 1.52-1.37 (m, 1H),1.17 (d, J=6.3 Hz, 3H). Compound 192: as an off-white solid. LCMS (ESI)[M+H]⁺=372.2; ¹HNMR(400 MHz, DMSO) δ 10.79 (s, 1H), 9.32 (s, 1H),8.48-8.36 (m, 2H), 8.28 (s, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.92 (s, 1H),6.55 (d, J=1.5 Hz, 1H), 6.34 (s, 2H), 2.83-2.61 (m, 2H), 2.30 (s, 3H),2.15-2.03 (m, 1H), 1.58-1.45 (m, 1H), 1.36 (dt, J=9.1, 6.1 Hz, 1H), 1.17(d, J=6.1 Hz, 3H).

Example 229(±)-cis-N-(8-amino-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide(Compound 152)

Step 1: 8-chloro-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-amine

A mixture of 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine (800 mg, 2.48mmol), (2,6-dichlorophenyl)boronic acid (1.42 g, 7.42 mmol),bis(tri-tert-butylphosphine)palladium(0) (127 mg, 0.25 mmol) and cesiumfluoride (1.13 g, 7.44 mmol) in dioxane (10 mL) and water (1 mL) wasstirred at 100° C. for 12 hours. The resulting solution was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluted with ethyl acetate/petroleum ether (1/3) to afford8-chloro-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-amine (820 mg,2.412 mmol) as a white solid. LCMS (ESI) [M+H]⁺=341.

Step 2:(±)-cis-N-[8-chloro-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl]-2-fluorocyclopropane-1-carboxamide

To a solution of8-chloro-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-amine (794 mg,2.32 mmol), cis-2-fluorocyclopropane-1-carboxylic acid (320 mg, 3.075mmol) and pyridine (1 mL, 12.42 mmol) in dichloromethane (10 mL) wasadded dropwise phosphorus oxychloride (560 mg, 3.65 mmol) at 0° C. Thereaction mixture was stirred for 30 min at room temperature. Thereaction was then quenched by water and then extracted withdichloromethane. The organic phase was dried over anhydrous sodium,filtered and concentrated under vacuum. The residue was purified byflash chromatography on silica eluted with ethyl acetate/petroleum ether(1:1) to affordcis-N-[8-chloro-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl]-2-fluorocyclopropane-1-carboxamide(763 mg, 1.79 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=427.

Step 3: (±)-trans-tert-butyl(6-(2,6-dichlorophenyl)-7-fluoro-3-(2-fluorocyclopropane-1-carboxamido)isoquinolin-8-yl)carbamate

A solution ofcis-N-[8-chloro-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl]-2-fluorocyclopropane-1-carboxamide(300 mg, 0.70 mmo), tert-butyl carbamate (2.5 g, 21.34 mmol),tris(dibenzylideneacetone)dipalladium (150 mg, 0.15 mmol), BrettPhos (75mg, 0.14 mmol), and cesium carbonate (930 mg, 2.85 mmol) in 1,4-dioxane(15 mL) was stirred for 2 h at 90° C. The resulting mixture was cooledto room temperature and then filtered. The filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silicaeluted with ethyl acetate/petroleum ether (3/2) to afford cis-tert-butyl(6-(2,6-dichlorophenyl)-7-fluoro-3-(2-fluorocyclopropane-1-carboxamido)isoquinolin-8-yl)carbamate(190 mg, 0.375 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=508.

Step 4:(±)-cis-N-[8-amino-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl]-2-fluorocyclopropane-1-carboxamide

To a solution of cis-tert-butylN-[6-(2,6-dichlorophenyl)-7-fluoro-3-[[2-fluorocyclopropane]amido]isoquinolin-8-yl]carbamate(170 mg, 0.33 mmol) and trifluoroacetic acid (1.6 mL, 21.541 mmol) indichloromethane (8 mL) was stirred for 1 h at 25° C. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-HPLC (Atlantis HILIC OBD, 19×150 mm 5 um; water (0.1%FA): CH₃CN(5%-23%) in 7 min) to afford(±)-cis-N-[8-amino-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl]-2-fluorocyclopropane-1-carboxamide(21.6mg, 0.053 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=408; ¹HNMR (400MHz, DMSO-d₆) δ 10.86 (s, 1H), 9.44 (s, 1H), 8.30 (s, 1H), 7.65 (d,J=8.1 Hz, 2H), 7.54-7.49 (m, 1H), 6.93 (d, J=5.9 Hz, 1H), 6.32 (s, 2H),5.04-4.83 (m, 1H), 2.31-2.19 (m, 1H), 1.68-1.66 (m, 1H), 1.19-1.17 (m,1H).

Example 2302-((6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 232)

Step 1:1-[4-(3-amino-7-chloro-6-isoquinolyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone

To a solution of 6-bromo-7-chloro-isoquinolin-3-amine (200 mg, 0.78mmol) in 1,4-dioxane (2 mL) was added1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone(234.1 mg, 0.93 mmol), potassium carbonate (321.5 mg, 2.33 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56.85 mg,0.08 mmol). The resulting suspension was stirred at 90° C. for 2 hours.After filtration, the filtrate was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford1-[4-(3-amino-7-chloro-6-isoquinolyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone(210 mg, 0.69 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=319.0.

Step 2:2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of1-[4-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone(200 mg, 0.66 mmol),2-bromo-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(265 mg, 0.99 mmol), t-BuBrettphos G3 (171 mg, 0.20 mmol), t-BuBrettphos(195 mg, 0.40 mmol), cesium carbonate (645 mg, 1.98 mmol) in 1,4-dioxane(20 mL) was stirred at 100° C. for 8 hours. The suspension was filteredthrough a pad of Celite. The mixture was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(110 mg, 0.019 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=510.

Step 3:2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A mixture of2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-chloro-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one (100 mg, 0.20 mmol) andtert-butyl carbamate (340 mg, 2.93 mmol),tris(dibenzylideneacetone)dipalladium-chloroformadduct (30 mg, 0.04mmol), Brettphos (40.0 mg, 0.07 mmol), cesium carbonate (180 mg, 0.55mmol) in 1,4-dioxane (10 mL) was stirred at 90° C. for 1 hours. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford 2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-chloro-7-fluoro-3soquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(100 mg, 0.20 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=591.

Step 4:2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-amino-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(105 mg, 0.18 mmol) in TFA (1 mL, 0.18 mmol) in dichloromethane (5 mL)was stirred at 15° C. for 2 hours. The resulting solution wasconcentrated under vacuum. The residue was purified by Prep-HPLC toprovide2-[[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-8-amino-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(27.8 mg, 0.057 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=492.2; ¹HNMR(400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 9.02 (s, 1H), 7.68 (s, 1H), 6.79-6.76(m, 1H), 6.09 (s, 1H), 5.94 (s, 3H), 4.97 (s, 2H), 4.64-4.55 (m, 1H),4.17-4.10 (m, 2H), 3.80-3.78 (m, 2H), 3.66-3.61 (m, 2H), 3.00-2.96 (m,2H), 2.56 (s, 1H), 2.51-2.50 (m, 1H), 2.07 (d, J=9.2 Hz, 3H), 1.12 (d,J=9.2 Hz, 6H).

Example 2312-((8-amino-6-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one(Compound 251)

Step 1: 1,4-dimethyl-3-nitro-pyrazole

A solution of 4-methyl-3-nitro-1H-pyrazole (500 mg, 3.93 mmol),iodomethane (837.9 mg, 5.9 mmol) and potassium tert-butoxide (484.6 mg,4.33 mmol) in tetrahydrofuran (20 mL) was stirred at 25° C. for 1 hour.The solvent was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford 1,4-dimethyl-3-nitro-pyrazole (450 mg, 3.18 mmol) as awhite solid. LCMS (ESI) [M+H]+=142.

Step 2: 1,4-dimethylpyrazol-3-amine

A solution of 1,4-dimethyl-3-nitro-pyrazole (530 mg, 3.76 mmol) andpalladium carbon (10%) (50 mg, 3.76 mmol) in methanol (20 mL) wasstirred at 20° C. for 1 hour. After filtration, the filtrate wasconcentrated under reduced pressure to afford1,4-dimethylpyrazol-3-amine (400 mg, 3.59 mmol) as light yellow oil.LCMS (ESI) [M+H]⁺=112.

Step 3: 3-(2,5-dimethylpyrrol-1-yl)-1,4-dimethyl-pyrazole

A solution of 1,4-dimethylpyrazol-3-amine (1.53 g, 13.77 mmol),2,5-hexanedione (3.14 g, 27.53 mmol) and p-toluenesulfonic acid (0.24 g,1.38 mmol) in toluene (60 mL) was stirred at 110° C. for 3 hours. Thesolvent was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(80/20) to afford 3-(2,5-dimethylpyrrol-1-yl)-1,4-dimethyl-pyrazole (1.5g, 7.92 mmol) as a gray solid. LCMS (ESI) [M+H]⁺=190.

Step 4: 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1,4-dimethyl-pyrazole

A solution of 3-(2,5-dimethylpyrrol-1-yl)-1,4-dimethyl-pyrazole (500 mg,2.64 mmol) in tetrahydrofuran (20 mL) was added n-Butyllithium (1.27 mL,3.17 mmol) at −78° C. The resulting solution was stirred for 1 hour at−78° C. Then iodine (671.03 mg, 2.64 mmol) was added and stirred at −78°C. for 10 minutes. The mixture was stirred at room temperature for 1hour. The reaction was quenched with saturated sodium thiosulfateaqueous. The resulting solution was extracted with ethyl acetate, driedwith anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(3/1) to afford 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1,4-dimethyl-pyrazole(385 mg, 1.22 mmol) as a light yellow oil. LCMS (ESI) [M+H]⁺=316.

Step 5: 5-iodo-1,4-dimethyl-pyrazol-3-amine

A solution of 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1,4-dimethyl-pyrazole(500 mg, 1.59 mmol), potassium hydroxide (444.23 mg, 7.93 mmol),hydroxylamine hydrochloride (1.09 g, 15.87 mmol) in ethanol (20 mL) andwater (20 mL) was stirred at 90° C. for 12 hours. The solvent wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(96/4) to afford 5-iodo-1,4-dimethyl-pyrazol-3-amine (281 mg, 1.18 mmol)as a white solid. LCMS (ESI) [M+H]⁺=238.

Step 6: tert-butylN-[6-(5-amino-2,4-dimethyl-pyrazol-3-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate

A solution of 5-iodo-1,4-dimethyl-pyrazol-3-amine (31.0 mg, 0.13 mmol),[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]horonicacid (67 mg, 0.13 mmol), terakis(triphenylphosphine)palladium (27.59 mg,0.03 mmol) and potassium carbonate (54.14 mg, 0.39 mmol) in 1,4-dioxane(3 mL) and water (0.3 mL) was stirred at 90° C. for 1 hour. The solventwas concentrated under vacuum to afford tert-butylN-[6-(5-amino-2,4-dimethyl-pyrazol-3-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate(50 mg, crude) as a brown solid. LCMS (ESI) [M+H]⁺=578.

Step 7:2-[[8-amino-6-(5-amino-2,4-dimethyl-pyrazol-3-yl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one

A solution of tert-butylN-[6-(5-amino-2,4-dimethyl-pyrazol-3-yl)-7-fluoro-3-[(6-isopropyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-8-isoquinolyl]carbamate (50.0 mg, 0.09 mmol)and 2,2,2-trifluoroacetic acid (1.0 mL) in dichloromethane (4 mL) wasstirred at 25° C. for 1 hour. The resulting solution was concentratedunder vacuum. The crude product was purified by Prep-HPLC [AtlantisHILIC OBD Column19×150 nm×50 um; water (10 mmol/L sodium bicarbonate andACN (20%-50%) in 7 min] to afford2-[[8-amino-6-(5-amino-2,4-dimethyl-pyrazol-3-yl)-7-fluoro-3-isoquinolyl]amino]-6-isopropyl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one(9.1 mg, 0.019 mmol) as a yellow solid. LCMS (ESI) [M+H]⁺=478; ¹HNMR(400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.09 (s, 1H), 7.69 (s, 1H), 6.75 (d,J=6.0 Hz, 1H), 6.13 (s, 2H), 5.98 (s, 1H), 4.98 (s, 2H), 4.65-4.55 (m,1H), 4.48 (s, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.45 (s, 3H), 2.98 (t, J=6.0Hz, 2H), 1.77 (s, 3H), 1.12 (d, J=6.0 Hz, 6H).

Example 232(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 383),(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 384),(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 385),(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide(Compound 386)

Step 1:2-[(benzyloxy)methyl]-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide

A solution of8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-amine (1 g, 3.48mmol), (1S,2S)-2-[(benzyloxy)methyl]-3-methylcyclopropane-1-carboxylicacid (1.15 g, 5.22 mmol), pyridine (2 mL, 24.847 mmol) indichloromethane (20 mL) was added phosphorus oxychloride (1.06 g, 6.90mmol) at 0° C. The resulting solution was stirred for 30 min at 0° C.and then quenched by water. The resulting solution was extracted withdichloromethane, dried with anhydrous sodium sulfate. After filtration,the filtrate was concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (10/1) to afford(1S,2S)-2-[(benzyloxy)methyl]-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(0.9 g, 53%) as a yellow solid.

Step 2: tert-butylN-(3-[[(2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of2-[(benzyloxy)methyl]-N-[8-chloro-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-3-methylcyclopropane-1-carboxamide(900 mg, 1.84 mmol), tert-butyl N-methylcarbamate (4.3 g, 32.78 mmol),Pd₂(dba)₃. CHCl₃ (380 mg, 0.37 mmol), BrettPhos (395 mg, 0.74 mmol),cesium carbonate (2.4 g, 7.37 mmol) in 1,4-dioxane (30 mL) was stirredfor 5 h at 100° C. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(10/1) to afford tert-butylN-(3-[[2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(500 mg, 48%) as a yellow solid. LCMS (ESI) [M+H]⁺=571.

Step 3: tert-butylN-(7-fluoro-3-[[2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of tert-butylN-(3-[[2-[(benzyloxy)methyl]-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(500 mg, 0.88 mmol) in methanol (20 mL)was added Pd(OH)₂/C (100 mg). Theresulting solution was stirred for 12 h at room temperature under H₂ (1atm). The reaction was filtered and concentrated under vacuum to affordtert-butylN-(7-fluoro-3-[[2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(220 mg, 52%) as a white solid. LCMS (ESI) [M+H]⁺=481.

Step 4: tert-butylN-(7-fluoro-3-[[2-[(methanesulfonyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of tert-butylN-(7-fluoro-3-[[(1S,2S)-2-(hydroxymethyl)-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 0.42 mmol) in dichloromethane (10 mL) was added triethylamine(70 mg, 0.69 mmol) and methanesulfonyl chloride (60 mg, 0.52 mmol) at 0°C. The resulting solution was stirred for 15 min at room temperature andthen concentrated under vacuum to afford tert-butylN-(7-fluoro-3-[[2-[(methanesulfonyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, crude) as a white solid. LCMS (ESI) [M+H]⁺=559.

Step 5: tert-butylN-(3-[[2-(cyanomethyl)-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate

To a solution of tert-butylN-(7-fluoro-3-[[2-[(methanesulfonyloxy)methyl]-3-methylcyclopropane]amido]-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(200 mg, 0.36 mmol) in dimethyl sulphoxide (10 mL) was added potassiumcyanide (46 mg, 0.71 mmol). The resulting solution was stirred for 3 hat 60° C. The resulting solution was diluted with water and thenextracted with ethyl acetate.The organic layers dried with anhydroussodium sulfate. After filtration, the filtrate was concentrated undervacuum to afford tert-butylN-(3-[[2-(cyanomethyl)-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(210 mg, crude) as a white solid. LCMS (ESI) [M+H]⁺=490.

Step 6:(1S,2S,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide,(1R,2R,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide,(1S,2S,3S)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide,(1R,2R,3R)—N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide

To a solution of tert-butylN-(3-[[2-(cyanomethyl)-3-methylcyclopropane]amido]-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-8-yl)carbamate(100 mg, 0.20 mmol) and TFA (3 ml) in 1,4-dioxane (5 mL) was stirred for2 h at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by Prep-HPLC (XBridge Shield RP18 OBDColumn, 5 μm, 19*150 mm; Water (0.05% NH₃H₂O) and ACN (15% ACN up to 40%in 15 min)) to afford the mixture. The mixture was isolated by SFC toafford four isomers (Cyclopropane stereochemistry: cyanomethyl trans toamide; methyl relative stereochemistry arbitrarily assigned; Allabsolute stereochemistry arbitrarily assigned): Compound 383: (2.4 mg,3%) as a yellow solid. Retention time: 3.83 min. (CHIRALPAK ID-30.46*10cm; 3 μm; MtBE(0.1% DEA):EtOH=70:30; 1.0 ml/min); LCMS(ESI) [M+H]⁺=390;¹HNMR (300 MHz, CD₃OD) δ 9.31(s, 1H), 8.48-8.41 (m, 2H), 8.31 (s, 1H),7.45-7.43 (d, J=5.1 Hz, 1H), 7.00-6.98 (d, J=6 Hz, 1H), 2.79-2.60 (m,2H), 2.31 (s, 3H), 1.88-1.85 (m, 1H), 1.83-1.69 (m, 2H), 1.34-1.20 (m,3H). Compound 384: (2.4 mg, 3%) as a yellow solid. Retention time: 5.64min (CHIRALPAK ID-30.46*10 cm; 3 μm; MtBE(0.1% DEA):EtOH=70:30; 1.0ml/min); LCMS(ESI) [M+H]⁺=390; ¹HNMR (300 MHz, CD₃OD) δ 9.31 (s, 1H),8.48-8.41 (m, 2H), 8.31 (s, 1H), 7.45-7.43 (d, J=5.1 Hz, 1H), 7.00-6.98(d, J=6 Hz, 1H), 2.79-2.60 (m, 2H), 2.31 (s, 3H), 1.88-1.85 (m, 1H),1.83-1.69 (m, 2H), 1.34-1.20 (m, 3H). Compound 385: (3.4 mg, 4%) as ayellow solid. Retention time: 4.636 min (CHIRALPAK IA-30.46*5 cm; 3 μm;Hex(0.1% DEA):EtOH=50:50; 1.0 ml/min); LCMS(ESI) [M+H]⁺=390; ¹HNMR (300MHz, CD₃OD) δ 9.31 (s, 1H), 8.48-8.41 (m, 2H), 8.31 (s, 1H), 7.45-7.43(d, J=5.1 Hz, 1H), 7.00-6.98 (d, J=6 Hz, 1H), 2.79-2.60 (m, 2H), 2.31(s, 3H), 1.88-1.85 (m, 1H), 1.83-1.69 (m, 2H), 1.34-1.20 (m, 3H).Compound 386: (2.7 mg, 3%) as a yellow solid. Retention time: 6.686 min(CHIRALPAK IA-30.46*5 cm; 3 μm; Hex(0.1% DEA):EtOH=50:50; 1.0 ml/min);LCMS(ESI) [M+H]⁺=390; ¹HNMR (300 MHz, CD₃OD) δ 9.31 (s, 1H), 8.48-8.41(m, 2H), 8.31 (s, 1H), 7.45-7.43 (d, J=5.1 Hz, 1H), 7.00-6.98 (d, J=6Hz, 1H), 2.79-2.60 (m, 2H), 2.31 (s, 3H), 1.88-1.85 (m, 1H), 1.83-1.69(m, 2H), 1.34-1.2 (m, 3H).

Compound Characterization: Chemical Example 233

Exemplary compounds of Formula I or Ia were prepared and characterized.The data are shown in Table A-1.

TABLE A-1 LCMS R_(T) (min); Cmpd Structure/ M + H⁺; ¹H NMR No. NameMethod (ppm)  1

1.842 368.1 C ¹H NMR (400 MHz, DMSO-d₆) δ: 11.12 (s, 1H), 9.35 (s, 1H),8.24 (s, 1H), 7.81 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0Hz, 1H), 6.88 (s, 1H), 6.54 (d, J = 1.2 Hz, 1H), 6.39 (s, 2H), 2.78-2.73(m, 1H), 2.29 (s, 3H), 2.16-2.11 (m, 1H), 1.62-1.57 (m, 1H), 1.45-1.44(m, 1H).  2

1.781 319.2 C ¹H NMR (400 MHz, DMSO-d₆) δ: 10.78 (s, 1H), 9.31(s, 1H),8.44 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.34 (d, J = 4.8Hz, 1H), 6.88 (s, 1H), 6.54 (s, 1H), 6.33 (s, 2H), 2.29 (s, 3H),2.07-2.04 (m, 1H), 0.83-0.80 (m, 4H).  3

1.216 353.1 A ¹H NMR (400 MHz, CD,OD) δ: 9.25 (s, 1H), 8.57 (d, J = 5.2Hz, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.02 (s,1H), 6.67 (d, J = 1.6 Hz, 1H), 4.99-4.95 (m, 0.5 H), 4.83-4.79 (m, 0.5H), 4.67 (s, 2H), 2.18-2.13 (m, 1H), 1.88-1.77 (m, 1H), 1.27-1.18 (m,1H).  4

1.819 337.0 C ¹H NMR (400 MHz, CDCl₃) δ: 9.05 (s, 1H), 8.54 (d, J = 4.8Hz, 1H), 8.48 (s, 2H), 8.26 (s, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.06 (d,J = 6.4 Hz, 1H), 4.45 (bs, 2H), 2.26 (s, 3H), 1.63-1.60 (m, 1H),1.16-1.14 (m, 2H), 0.94-0.92 (m, 2H).  5

1.668 344.1 F ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (s, 1H), 8.55 (d, J = 5.2Hz, 1H), 8.47 (s, 1H), 8.46 (s, 1H), 8.25 (s, 1H), 7.27 (d, J = 5.2 Hz,1H), 6.99 (s, 1H), 5.43 (bs, 2H), 2.28 (s, 3H), 1.60-1.57 (m, 1H),1.17-1.15 (m, 2H), 0.97-0.96 (m, 2H).  6

1.724 333.1 H ¹H NMR (400 MHz, CD₃OD) δ: 9.27 (s, 1H), 8.28 (s, 1H),8.18 (s, 1H), 8.00 (s, 1H), 7.12 (s, 1H), 4.00 (s, 3H), 1.33-1.32 (m,1H), 1.04-1.03 (m, 2H), 0.95-0.92 (m, 2H).  7

1.760 262.0 F ¹H NMR (400 MHz, DMSO-d₆) δ: 10.84(s, 1H), 9.39(s, 1H),8.26(s, 1H), 7.45(d, J = 8.4 Hz, 1H), 6.97(d, J = 8.4 Hz, 1H), 6.37(s,2H), 2.02-2.06(m, 1H), 0.80- 0.83(m, 4H).  8

1.661 253.0 F ¹H NMR (400 MHz, CD₃OD) δ: 9.30 (s, 1H), 8.30 (s, 1H),7.44 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 1.93-1.97 (m, 1H),1.01-1.05 (m, 2H), 0.91-0.95 (m, 2H). 13

1.493 395.1 E ¹H NMR (400 MHz, CD₃OD) δ: 9.27 (s, 1H), 8.77 (s, 1H),8.52 (brs, 1H), 8.36 (s, 1H), 7.09 (s, 1H), 6.72 (s, 1H), 4.99-4.79 (m,1H), 3.04 (s, 3H), 2.65 (s, 3H), 2.18- 2.13 (m, 1H), 1.88-1.78 (m, 1H),1.27-1.19 (m, 1H). 14

1.335 376.1 C ¹H NMR (400 MHz, CD₃OD) δ: 9.23 (s, 1H), 8.30 (s, 1H),8.16 (s, 1H), 7.59-7.47 (m, 2H), 7.03 (s, 1H), 6.76 (s, 1H), 4.99- 4.78(m, 1H), 2.40 (s, 3H), 2.20-2.12 (m, 1H), 1.87-1.76 (m, 1H), 1.27-1.17(m, 1H). 15

1.566 364.1 C ¹H NMR (400 MHz, CD₃OD) δ: 9.28 (s, 1H), 9.00 (s, 1H),8.78 (s, 1H), 8.37 (s, 1H), 7.18 (s, 1H), 6.80 (s, 1H), 4.99-4.95- 4.78(m, 1H), 2.21-2.08 (m, 2 H), 1.88- 1.76 (m, 1H), 1.27-1.17 (m, 3H),1.12-1.06 (m, 2H). 16

1.42 377.2 E ¹H NMR (400 MHz, CD₃OD) δ: 9.25 (s, 1H), 8.43 (s, 1H), 8.33(s, 2H), 7.06 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 4.99--4.79 (m, 1H),2.65 (s, 3H), 2.18-2.13 (m, 1H), 1.88- 1.77 (m, 1H), 1.27-1.18 (m, 1H).17

1.57 354.1 E ¹H NMR (400 MHz, CD₃OD) δ: 9.17(s, 1H), 8.26 (s, 1H), 7.69(s, 1H), 7.07 (s, 1H), 6.83 (d, J = 0.9 Hz, 1H), 4.99-4.92 (m, 0.5 H),4.83-4.79 (m, 0.5 H), 3.45-3.44 (m, 1H), 2.17-2.13 (m, 1H), 1.87-1.79(m, 1H), 1.37-1.35 (d, J = 6.8 Hz, 6H), 1.27-1.18 (m, 1H). 18

1.44 381.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.24 (s, 1H), 8.32 (s, 1H), 7.58(s, IH). 6.96 (s, 1H), 6.63 (d, J = 0.8 Hz, 1H), 6.49 (s, 1H), 4.97-4.80(m, 1H), 4.108(q, J = 7.2 Hz, 2H), 2.17-2.14(m, 1H), 2.05 (s, 3H), 1.86-1.79 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.25-1.20 (m, 1H). 19

1.45 353.1 B ¹H NMR (400 MHz, DMSO-d₆) δ: 11.53- 11.49 (m, 1H), 10.81(s, 1H), 9.32 (s, 1H), 8.27 (s, 1H), 7.28 (s, 1H), 6.85 (s, 1H), 6.49(s, 1H), 6.34 (s, 2H), 6.19 (s, 1H), 5.03-4.83 (m, 1H), 2.28-2.22 (m,1H), 1.91 (s, 3H), 1.71-1.63 (m, 1H), 1.21-1.14 (m, 1H). 20

1.167 325.2 B ¹H NMR (400 MHz, CD₃OD) δ: 8.94 (s, 1H), 7.92 (s, 1H),7.78 (s, 1H), 7.35 (s, 1H), 7.06 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H),3.92-3.85 (m, 1H), 3.85 (s, 3H), 1.15 (d, J = 6.4 Hz, 6H). 21

1.479 383.1 A ¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 9.37 (s, 1H),8.36 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 7.62 (d, J = 3.2 Hz, 1H), 7.28(s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 1.2 Hz, 1H), 6.69 (d, J= 3.2 Hz, 1H), 6.44 (s, 2H), 3.88 (s, 3H), 2.80-2.75 (m, 1H), 2.18-2.13(m, 1H), 1.63-1.58 (m, 1H), 1.47-1.42 (m, 1H). 22

1.392 369.1 A ¹H NMR (400 MHz, DMSO-d₆) δ: 11.80 (s, 1H), 11.11(s, 1H),9.36 (s, 1H), 8.31 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.56 (t, J = 2.8Hz, 1H), 7.28 (s, 1H), 7.23 (d,J = 4.8 Hz, 1H), 7.04 (d, J = 1.2 Hz,1H), 6.67 (q, J = 1.7 Hz, 1H), 6.42 (s, 2H), 2.79-2.75 (m, 1H),2.17-2.12 (m, 1H), 1.62-1.57 (m, 1H), 1.47-1.42 (m, 1H). 23

1.528 388.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.30 (s, 1H), 8.32 (s, 1H),7.58 (d, J = 9.2 Hz, 1H), 6.96 (s, 1H), 6.64 (d, J = 9.2 Hz, 1H), 6.56(s, 1H), 3.30 (s, 3H), 2.67-2.62 (m, 1H), 2.22-2.10 (m, 3H), 1.62-1.53(m, 2H), 1.3 (t, J = 7.6 Hz, 3H). 24

1.543 367.1 C ¹H NMR (400 MHz, CD₃OD) δ: 9.21 (s, 1H), 8.28 (s, 1H),7.58(d, J = 6.8 Hz, 1H), 6.91 (s, 1H), 6.58 (s, 1H), 6.40 (d, J = 6.8Hz, 1H), 4.98-4.78 (m, 1H), 3.59 (s, 3H), 2.17-2.13 (m, 1H), 2.01 (s,3H), 1.87-1.76 (m, 1H), 1.26-1.17 (m, 1H). 25

1.524 367.1 B ¹H NMR (400 MHz, CD₃OD) δ: 9.21 (s, 1H), 8.21 (s, 1H),7.58 (d, J = 6.8 Hz, 1H), 6.89 (s, 1H), 6.58 (s, 1H), 6.40 (d, J = 6.8Hz, 1H), 4.97-4.78 (m, 1H), 3.59 (s, 3H), 2.49-2.39 (m, 1H), 2.01 (s,3H), 1.55-1.47 (m, 1H), 1.41-1.36 (m, 1H). 26

1.738 367.0 G ¹HNMR (400 MHz, CD₃OD) δ: 9.22 (s, 1H), 8.29 (s, 1H), 7.59(d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.71(d, J = 8.0 Hz, 1H), 6.69(d, J =1.6 Hz, 1H), 4.99--4.80 (m, 1H), 3.96 (s, 3H), 2.44 (s, 3H), 2.18-2.14(m, 1H), 1.86-1.79 (m, 1H), 1.25-1.22 (m, 1H). 27

1.348 353.0 G ¹H NMR (400 MHz, CD₃OD) δ: 9.20(s, 1H), 8.29(s, 1H),7.62(d, J = 9.2 Hz, 1H), 6.97(s, 1H), 6.65 (d, J = 1.2 Hz, 1H), 6.48(d,J = 9.2 Hz, 1H), 4.98--4.80 (m, 1H), 2.35(s, 3H), 2.18-2.13 (m, 1H),1.86-1.79 (m, 1H), 1.24-1.20 (m, 1H). 28

1.417 326.7 G ¹H NMR (400 MHz, CD₃OD) δ: 9.14 (s, 1H), 8.27 (s, 1H),7.81(s, 1H), 7.14 (s, 1H), 6.90 (d, J = 1.6 Hz, 1H), 4.99-4.79 (m, 1H),2.52 (s, 3H), 2.19-2.12 (m, 1H), 1.87- 1.79 (m, 1H), 1.25-1.20 (m, 1H).30

1.401 329.7 C ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.24 (s, 1H), 6.99(s, 1H), 6.69 (s, 1H), 4.99- 4.78 (m, 1H), 3.86-3.76 (m, 2H), 3.51-3.47(m, 1H), 2.81-2.74 (m, 1H), 2.59-2.53 (m, 1H), 2.14-2.11 (m, 1H),1.79-1.73 (m, 1H), 1.22-1.20 (m, 1H). 31

1.565 381.7 C ¹HNMR (400 MHz, CD₃OD) δ: 9.25 (s, 1H), 8.3l(s, 1H), 8.30(s, 1H) 7.56 (s, 1H), 6.99 (s, 1H), 6.67(d, J = 1.6 Hz, 1H), 4.98-4.75(m, 1H), 4.75 (s, 2H), 2.74 (q, J = 7.2 Hz, 2H), 2.18-2.15 (m, 1H),1.88-1.85 (m, 1H), 1.23-1.20 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H). 32

1.381 344.1 B ¹H NMR (400 MHz, DMSO-d₆) δ: 11.16 (s, 1H), 9.34 (s, 1H),8.44 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.34 (d, J = 4.8Hz, 1H), 6.91 (s, 1H), 6.57 (d, J = 1.6 Hz, 1H), 6.38 (s, 2H), 2.76-2.74(m, 1H), 2.29 (s, 3H), 2.15-2.11 (m, 1H), 1.60-1.44 (m, 1H), 1.43-1.41(m, 1H). 37

1.540 345.1 C ¹H NMR (400 MHz, DMSO-d₆) δ: 10.74 (s, 1H), 9.19 (s, 1H),8.19 (s, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 6.32(s, 2H), 5.01-4.83 (m, 1H), 4.71- 4.68 (m, 1H), 4.58-4.54 (m, 1H), 4.06-4.03 (m, 1H), 2.28-2.21 (m, 1H), 1.71- 1.61 (m, 1H), 1.29 (d, J = 6.0Hz, 3H), 1.19-1.12 (m, 1H). 38

1.573 380.1 B ¹H NMR (400 MHz, DMSO-d₆) δ: 11.15 (s, 1H), 9.41 (s, 1H),8.96 (d, J = 4.4 Hz, 1H), 8.28 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.95(d, J = 8.4 Hz, 1H), 7.82-7.78 (m, 1H), 7.62-7.58 (m, 1H), 7.51 (d, J =4.4 Hz, 1H), 7.07 (s, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.49 (s, 2H),2.77-2.72 (m, 1H), 2.15- 2.11 (m, 1H), 1.60-1.58 (m, 1H), 1.45- 1.40 (m,1H). 39

1.540 366.2 F ¹H NMR (400 MHz, DMSO-d₆) δ: 10.80 (s, 1H), 9.30 (s, 1H),8.24 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 6.79 (s, 1H), 6.48 (s, 1H),6.31 (s, 2H), 5.21 (s, 2H), 5.02-4.84 (m, 1H), 2.46-2.41 (m, 2H),2.27-2.24 (m, 1H), 1.69-1.62 (m, 1H), 1.18-1.14 (m, 1H), 0.98 (t, J = 76 Hz, 3H). 40

1.450 322.2 F ¹H NMR (400 MHz, CD₃OD) δ: 9.23 (s, 1H), 8.40 (d, J = 5.2Hz, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.39 (d, J = 5.2 Hz, 1H), 6.99 (s,1H), 6.68 (d, J = 1.2 Hz, 1H), 3.05 (t, J = 6.8 Hz, 2H), 2.66 (t, J =6.8 Hz, 2H), 2.37 (s, 3H). 41

1.530 354.2 B ¹H NMR (400 MHz, CD₃OD) δ: 9.43 (s, 1H), 8.39 (s, 1H),7.70 (s, 1H), 7.29 (s, 1H), 7.03 (s, 1H), 5.10-5.06 (m, 1H), 3.62- 3.57(m, 1H), 2.20-2.17(m, 1H), 1.99- 1.89(m, 1H), 1.42 (d, J = 6.8 Hz, 6H),1.39-l.30(m, 1H). 42

1.590 354.2 B ¹H NMR (400 MHz, CD₃OD) δ: 9.41 (s, 1H), 8.37 (s, 1H),7.68 (s, 1H), 7.30 (s, 1H), 7.03 (s, 1H), 5.08-5.05 (m, 1H), 3.62- 3.58(m, 1H), 2.46-2.38 (m, 1H), 1.75-1.65 (m, 1H), 1.58-1.50 (m, 1H), 1.42(dJ = 6.8 Hz, 6H). 43

1.385 353.1 A 1H NMR (400 MHz, CD₃OD) δ: 9.27 (s, 1H), 8.36 (s, 1H),7.59 (dd, J = 6.8, 9.2 Hz, 1H), 7.09 (s, 1H), 6.67 (d, J = 1.6 Hz, 1H),6.62(dd, J = 1.2, 9.2 Hz, 1H), 6.42 (dd, J = 1.2, 6.8 Hz, 1H), 4.99-4.79(m, 1H), 3.46 (s, 3H), 2.19-2.13 (m, 1H), 1.87-1.78 (m, 1H), 1.27-1.18(m, 1H). 44

1.513 383.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.24 (s, 1H), 8.27 (s, 1H),8.03 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 6.76 (d, J = 1.2Hz, 1H), 2.65-2.64 (m, 1H), 2.39 (s, 3H), 2.14-2.09 (m, 1H), 1.62-1.55(m, 2H). 45

1.372 401.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.23 (s, 1H), 8.25 (s, 1H),8.03 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 6.75 (s, 1H),2.42-2.38 (m, 4H), 2.25-2.20 (m, 1H), 1.44-1.40 (m, 2H). 46

1.253 353.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.22 (s, 1H), 8.44 (d, J = 6.0Hz, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 7.21 (d, J = 6.0 Hz, 1H), 7.19 (s,1H), 6.88 (d, J = 1.6 Hz, 1H), 4.98-4.80 (m, 1H), 3.96 (s, 3H),2.19-2.14 (m, 1H), 1.88-1.78 (m, 1H), 1.27-1.18 (m, 1H). 47

1.295 353.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.22 (s, 1H), 8.44 (d, J = 6.0Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7 21 (d, J = 6.0 Hz, 1H), 7.17 (s,1H), 6.88 (d, J = 0.8 Hz, 1H), 4.99-4.78 (m, 1H), 3.96 (s, 3H),2.50-2.40 (m, 1H), 1.55-1.49 (m, 1H), 1.42-1.37 (m, 1H). 48

1.625 353.1 I ¹H NMR (400 MHz, DMSO-d₆) 8: 11.26 (s, 1H), 10.47(s, 1H),9.25 (s, 1H), 8.17 (s, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.74 (s, 1H), 6.47(s, 1H), 6.13 (d, J = 8.8 Hz, 1H), 5.91 (s, 2H), 5.00-4.76 (m, 1H),2.27-2.23 (m, 1H), 2.00 (s, 3H), 1.74-1.61 (m, 1H), 1.18- 1.12 (m, 1H).49

1.422 355.1 D ¹H NMR (400 MHz, CD₃OD) δ: 9.25 (s, 1H), 8.39 (d, J = 1.2Hz, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 7.01 (s, 1H), 6.68 (d, J = 1.6 Hz,1H), 4.99-4.78 (m, 1H), 2.31 (d, J = 2.0 Hz, 3H), 2.18-2.13 (m, 1H),1.87-1.77 (m, 1H), 1.26-1.21 (m, 1H). 50

1.273 323.0 A ¹H NMR (400 MHz, CD₃OD) δ: 9.23 (s, 1H), 8.89 (d, J = 1.6Hz, 1H), 8.56 (dd, J = 1.6, 4.8 Hz, 1H), 8.37 (s, 1H), 8.21-8.18 (m,1H), 7.56 (dd, J = 4 8, 8.0 Hz, 1H), 7.34 (s, 1H), 7.01(d, J = 1.2 Hz,1H), 4.99- 4.79 (m, 1H), 2.20-2.13 (m, 1H), 1.88-1.78 (m, 1H),1.27-1.19(m, 1H). 51

1.338 344.2 D ¹H NMR (400 MHz, CD₃OD) δ: 9.26 (s, 1H), 8.47 (s, 1H),8.41 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.00(s, 1H), 6.69 (d, J = 1.2 Hz, 1H), 2.64- 2.63(m, 1H), 2.34 (s, 3H),2.12-2.10(m, 1H), 1.60-1.53(m, 2H). 52

1.330 362.1 A ¹H NMR (400 MHz, CD₃OD) δ: 9.32 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.41(s, 1H), 8.33 (s, 1H), 7.42 (d, J = 5.2 Hz, 1H), 6.99 (d, J= 6.4 Hz, 1H), 2.65-2.61 (m, 1H), 2.30 (s, 3H), 2.14-2.09 (m, 1H),1.61-1.52 (m, 2H). 54

1.669 400.1 B ¹H NMR (400 MHz, DMSO-d₆) δ: 11.14(s, 1H), 9.36 (s, 1H),8.26 (s, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.61(s, 1H),6.35 (s, 2H), 2.83-2.78 (m, 1H), 2.30 (s, 3H), 2.21-2.16 (m, 1H),1.66-1.62 (m, 1H), 1.51-1.46 (m, 1H). 55

1.652 356.7 C ¹H NMR (400 MHz, CD₃OD) δ: 9.15 (s, 1H), 8.26 (s, 1H),7.07-7.04 (m, 1H), 6.85- 6.84 (m, 1H), 5.00-4.78 (m, 1H), 4.43-4.35 (m,1H), 2.67-2.54 (m, 2H), 2.43-2.34 (m, 1H), 2.20-2.10 (m, 1H), 1.97-1.69(m, 3H), 1.55-1.47 (m, 1H), 1.26-1.17 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H)56

1.956 402.2 C ¹H NMR (400 MHz, CD₃OD) δ: 9.24 (s, 1H), 8.26 (s, 1H),7.94 (s, 1H), 6.95 (s, 1H), 6.76 (s, 1H), 6.67 (d, J = 1.6 Hz, 1H),4.35(q, J = 6.8 Hz, 2H), 2.69-2.63 (m, 3H), 2.14-2.09 (m, 1H), 1.61-1.53(m, 2H), 1 42 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H) 57

1.532 346.8 H ¹H NMR (400 MHz, CD₃OD) δ: 9.19 (s, 1H), 8.27 (s, 1H),7.06 (s, 1H), 6.98 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 3.66 (s, 3H),2.67-2.60 (m, 1H), 2.45 (s, 3H), 2.13-2.04 (m, 1H), 1.63-1.50 (m, 2H).59

1.605 337.1 C ¹H NMR (400 MHz, CD₃OD) δ: 9.25 (s, 1H), 8.48 (s, 1H),8.43 (d, 7 = 4.8 Hz, 1H), 8.33 (s, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.02(s, 1H), 6.69 (d, J = 1.2 Hz, 1H), 4.99-4.79 (m, 1H), 2.35 (s, 3H),2.20-2.12 (m, 1H), 1.87-1.77 (m, 1H), 1.27-1.18 (m, 1H). 60

1.75 394.2 B ¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 9.35 (s, 1H),8.75 (d, J = 5.2 Hz, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 7.64 (d, J = 5.6Hz, 1H), 6.87 (s, 1H), 6.53 (s, 1H), 6.41 (s, 2H), 2.77-2.50 (m, 1H),2.14-2.10 (m. 1H), 1.77 (t, J = 19.2 Hz, 1H), 1.61- 1.58 (m, 1H),1.44-1.43 (m, 1H). 61

1.490 378.2 C ¹H NMR (400 MHz, DMSO-d₆) δ: 10.62 (s, 1H), 9.30 (s, 1H),8.45 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.35 (d, J = 4.8Hz, 1H), 6.92 (s, 1H), 6.56 (s, 1H), 6.33(s, 2H), 3.71-3.63 (m, 2H),3.22-3.20 (m, 1H), 3.12-3.10 (m, 2H), 2.78-2.75 (m, 2H), 2.41-2.40 (m,2H), 2.30 (s, 3H). 62

1.759 350.1 C ¹H NMR (400 MHz, DMSO-d₆) δ: 9.34 (s, 1H), 8.47 (s, 1H),8.28 (s, 1H), 7.09 (s, 1H), 6.74 (d, J = 1.6 Hz, 1H), 6.52 (s, 2H), 6.08(d, J = 1.6 Hz, 1H), 2.78-2.74 (m, 1H), 2.40 (s, 3H), 2.17-2.12 (m, 1H),1.62- 1.60 (m, 1H), 1.46-1.42 (m, 1H) 63

1.950 424.2 F ¹H NMR (400 MHz, CD₃OD) δ: 9.26 (s, 1H), 8.28 (s, 1H),8.06 (s, 1H), 7.58 (t, J = 73.2 Hz, 1H), 6.97 (s, 2H), 6.67 (s, 1H),2.71 (q, J = 7.6 Hz, 2H), 2.68-2.65 (m, 1H), 2.14-2.09 (m, 1H),1.63-1.52 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). 65

1.409 374.2 G ¹H NMR (400 MHz, CD₃OD) δ: 9.26 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.01 (s,1H), 6.70 (d, J= 1.2 Hz, 1H), 3.70 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 6.8Hz, 2H), 2.70-2.61 (m, 1H), 2.17-2.06 (m, 1H), 1.66-1.49 (m, 2H). 66

2.808 351.1 J ¹H NMR (400 MHz, DMSO-d₆) δ: 10.80 (s, 1H), 9.32 (s, 1H),8.49 (d, J = 5.1 Hz, 1H), 8.39-.35 (m, 1H), 8.27 (s, 1H), 7.38 (d, J =5.2 Hz, 1H), 6.88 (s, 1H), 6.53 (d, J = 1.5 Hz, 1H), 6.34 (s, 2H),5.04-4.81 (m, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.26 (dq, J = 14.1, 7.1 Hz,1H), 1.73 - 1.59 (m, 1H), 1.17 (ddt, J = 13.1, 9.8, 6.7 Hz, 1H),1.13-1.06 (m, 3H). 67

2.999 358.1 J ¹H NMR (400 MHz, DMSO-d₆) δ: 11.10 (s, 1H), 9.34 (s, 1H),8.49 (d, J = 5.1 Hz, 1H), 8.40-8.34 (m, 1H), 8.23 (s, 1H), 7.41- 7.35(m, 1H), 6.88 (s, 1H), 6.55 (d, J = 1.5 Hz, 1H), 6.38 (s, 2H), 2.80-2.72 (m, 1H), 2.61 (q, J = 7.5 Hz, 2H), 2.13 (ddd, J = 9.3, 6.1, 4.3Hz, 1H), 1.59 (ddd, J = 8.6, 6.0, 4.4 Hz, 1H), 1.43 (ddd, J = 9.3, 5.9,4.4 Hz, 1H), 1.09 (t, J = 7.6 Hz, 3H). 68

2.745 358.2 J ¹H NMR (400 MHz, DMSO-d₆) δ: 11.06 (d, J = 20.0 Hz, 1H),9.34 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.37 (d, J = 0.5 Hz, 1H), 8.30(s, 1H), 7.38 (dt, J = 9.0. 4.5 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J = 1.5Hz, 1H), 6.37 (s, 2H), 2.62 (dt, J = 15.0, 7.5 Hz, 3H), 2.30- 2.22 (m,1H), 1.51-1.40 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H). 69

4.401 369.1 J ¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 9.36 (s, 1H),8.59 (s, 1H), 8.26 (s, 1H), 8.06 (d, J = 0.7 Hz, 1H), 6.97 (d, J = 0.6Hz, 1H), 6.57 (d, J = 1.5 Hz, 1H), 6.44 (s, 2H), 2.81-2.71 (m, 1H), 2.36(s, 3H), 2.13 (ddd, J = 9.3, 6.1, 4.3 Hz, 1H), 1.59 (ddd, J = 8.6, 6.0,4.4 Hz, 1H), 1.43 (ddd, J = 9.3, 5.9, 4.4 Hz, 1H). 70

3.847 396.1 J ¹H NMR (400 MHz, DMSO-d₆) δ: 11.14 (s, 1H), 9.40 (s, 1H),9.17 (t, J = 1.5 Hz, 1H), 9.14 (d, J = 1.8 Hz, 1H), 9.07 (s, 1H), 8.29(s, 1H), 7.08 (s, 1H), 6.71 (d, J = 1.5 Hz, 1H), 6.47 (s, 2H), 2.82-2.73(m, 4H), 2.14 (ddd, J = 9.3, 6.1, 4.3 Hz, 1H), 1.59 (ddd, J = 8.6, 6.0,4.5 Hz, 1H), 1.43 (ddd, J = 9.2, 5.9, 4.4 Hz, 1H).

Example 234

Additional exemplary compounds of Formula I or Ia were prepared (TablesA-2, A-3 and A-4); and the binding data are shown in Tables B1-1 andB1-2.

TABLE A-2 LCMS R_(T) (min); Compound M + H^(+;) No. Structure Method 71trans enantiomer 1

2.999 358.1 N

trans-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 72 transenantiomer 2

2.999 358.1 N

trans-N-(8-amino-6-(4-ethylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 73 transenantiomer 1

1.38 344.1 E

trans-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 74 transenantiomer 2

1.38 344.1 E

trans-N-(8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 75 trans racemic

2.76 383.1 N

(±)-trans-N-(8-amino-6-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 76 trans racemic

3.09 384.1 N

(±)-trans-N-(8-amino-6-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 77

78 Trans racemic

n/a

(±)-trans-N-(8-amino-6-(6- methylimidazo[1,2-a]pyridin-7-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 79 Trans racemic

n/a

(±)-5-(8-amino-3-((trans)-2- cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)-N,1-dimethyl- 1H-pyrazole-3-carboxamide 80Trans Racemic

1.65 369.1 C

(±)-trans-N-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide81 Trans Racemic

n/a

(±)-trans-N-(8-amino-6-(3-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide 82Trans racemic

n/a

(±)-trans-N-(8-amino-6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1- carboxamide 85 Trans racemic

2.32 349.1 N

(±)-trans-N-(8-amino-6-(4-methylpyridin-3- yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide 86 Trans racemic

2.70 384.1 N

(±)-trans-N-(8-amino-6-(2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 87 Trans racemic

1.31 360.1 C

(±)-trans-N-(8-amino-6-(1-methyl-4-oxo-1,4-dihydropyridin-2-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide88 Trans racemic

1.31 358.1 C

(±)-trans-N-(8-amino-7-methyl-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide89 Trans racemic

1.67 378.1 C

(±)-trans-N-(8-amino-7-chloro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide90 Trans racemic

1.64 373.2 C

(±)-trans-N-(8-amino-6-(4- (dimethylamino)pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 91 Trans racemic

1.80 468.1 C

(±)-4-(8-amino-3-((trans)-2- cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)-3-methyl-N-(2,2,2-trifluoroethyl)benzamide 92 Trans Enantiomer 1

1.67 400.1 E

trans-N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 93 Trans Enantiomer 2

1.66 400.1 E trans-N-(8-amino-6-(5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 94 Trans Enantiomer 1

n/a

trans-N-(8-amino-6-(4-(2- hydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 95 Trans Enantiomer 2

1.41 374.2 C trans-N-(8-amino-6-(4-(2-hydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 96

1.30 349.2 C

(±)-trans-N-(8-amino-6-(4-methylpyridin-3- yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide 97 trans racemic

1.65 369.1 E

(±)-trans-N-(8-amino-7-cyano-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide98

n/a 99 trans racemic

1.67 400.2 C

(±)-3-(8-amino-3-((trans)-2- cyanocyclopropane-1-carboxamido)isoquinolin-6-yl)-N,4- dimethylbenzamide 100  trans racemiccyclopropyl

3.58 366.1 N

(±)-trans-N-(8-amino-6-(5,5-dimethyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide101  trans racemic cyclopropyl; S-enantiomer at isopropyl center

3.89 380.1 N

(±)-trans-N-(8-amino-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide102  trans racemic

2.53 377.1 N

(±)-trans-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide103  trans racemic cyclopropyl; R-enantiomer at isopropyl center

3.31 352.1 N

(±)-trans-N-(8-amino-6-((R)-4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide104  Removed 105  trans racemic

1.27 363.1 E

(±)-trans-N-(8-amino-6-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide 106  trans racemic

n/a

(±)-trans-N-(8-amino-5,7-difluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide107  trans racemic

3.847 396.1 J

(±)-trans-N-(8-amino-6-(8-methylpyrido[2,3-b]pyrazin-7-yl)isoquinolin-3-yl)-2- cyanocyclopropane-1-carboxamide 108 S,S-Cis-F- cyclopropyl; racemic at methyl center

1.538 345.1 E

cis-N-(8-amino-6-(4-methyl-2-oxooxazolidin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane- 1-carboxamide

TABLE A-3 LCMS R_(T) (min), Compound M + H^(+,) No. Structure/Namemethod ¹H NMR (ppm) 109

1.646 383.7 C ¹H NMR(400 MHz, CD₃OD) δ 9.26 (s, 1H), 8.37 (s, 1H), 8.30(s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.04 (s, 1H), 6.74(s, 1H), 2.66-2.64 (m, 1H), 2.27 (s, 3H), 2.15-2.10 (m, 1H), 1.61- 1.57(m, 2H). 110

1.543 390.7 C ¹H NMR(400 MHz, CD₃OD) δ 9.25 (s, 1H), 8.32 (s, 1H), 7.15(s, 1H), 6.84 (s, 1H), 6.80 (d, J = 1.2 Hz, 1H), 3.99 (s, 3H), 2.93 (s,3H), 2.65-2.62 (m, 1H), 2.15-2.10 (m, 1H), 1.62-1.48 (m, 2H). 113

1.593 369.1 G (racemate) Enantiomer #1: ¹H NMR (400 MHz DMSO-d₆) δ 11.32(s, 1H), 9.55 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.27 (s,1H), 7.44 (s, 2H), 7.40 (d, J = 5.2 Hz, 1H), 6.93 (s, 1H), 2.78- 2.75(m, 1H), 2.22 (s, 3H), 2.19-2.13 (m, 1H), 1.64-1.60 (m, 1H), 1.46-1.42(m, 1H). Enantiomer #2: 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.55(s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.42 (s,2H), 7.40 (d, J = 5.2 Hz, 1H), 6.93 (s, 1H), 2.78- 2.75 (m, 1H), 2.22(s, 3H), 2.19-2.13 (m, 1H), 1.64-1.60 (m, 1H), 1.46-1.42 (m, 1H). 115

1.70 358.1 C ¹H NMR (400 MHz, CD₃OD) δ 9.31 (s, 1H), 8.45 (d, J = 5.2Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.42 (d, J = 5.2 Hz, 1H), 6.90 (s,1H), 2.66-2.62 (m, 1H), 2.16 (s, 3H), 2.13-2.08 (m, 1H), 1.98 (s, 3H),1.61-1.52 (m, 2H). 116

1.64 373.2 C ¹H NMR (400 MHz, CD₃OD) δ 9.21 (s, 1H), 8.26 (s, 1H), 8.17(d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.07 (s, 1H), 6.93 (d, J = 6.0 Hz,1H), 6.80 (d, J = 1.2 Hz, 1H), 2.77 (s, 6H), 2.65-2.62 (m, 1H),2.14-2.09 (m, 1H), 1.62-1.52 (m, 2H). 117

1.310 360.1 G ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.37 (s, 1H),8.27 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.54-6.51 (m, 3H),6.14 (dd, J = 2.8, 7.6 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 3.41 (s, 3H),2.77-2.73 (m, 1H), 2.17-2.12 (m, 1H), 1.62-1.57 (m, 1H), 1.45-1.41 (m,1H). 118

1.268 363.1 A ¹HNMR (400 MHz, CD₃OD) δ 9.19 (s, 1H), 8.26 (s, 1H), 7.12(s, 1H), 6.85 (s, 1H), 4.63 (s, 2H), 2.67-2.62 (m, 1H), 2.38 (s, 3H),2.14-2.09 (m, 1H), 1.61- 1.53 (m, 2H). 119

1.302 349.2 B (racemate) Enantiomer #1: ¹H NMR (400 MHz, DMSO) δ: 10.70(s, 1H), 9.30 (s, 1H), 8.44 (m, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.43(m, 1H), 6.88 (s, 1H), 6.54 (s, 1H), 6.31 (s, 2H), 4.66 (m, 1H), 2.29(s, 3H), 1.97 (m, 1H), 1.50 (m, 1H), 1.01 (m, 1H), 0.79 (m, 1H).Enantiomer #2: ¹H NMR (400 MHz, DMSO) δ: 10.66 (s, 1H), 9.30 (s, 1H),8.48 (m, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.35 (m, 1H), 6.88 (s, 1H),6.54 (s, 1H), 6.31 (s, 2H), 4.66 (m, 1H), 2.30 (s, 3H), 1.97 (m, 1H),1.49 (m, 1H), 1.01 (m, 1H), 0.79 (m, 1H). 122

1.69 387.1 B ¹H NMR (400 MHz, CD₃OD) δ 9.27 (s, 1H), 8.07 (s, 1H), 8.04(s, 1H), 7.19 (s, 1H), 6.92 (s, 1H), 2.63-2.61 (m, 1H), 2.20-2.15 (m,1H), 1.65-1.59 (m, 2H). 123

1.65 396.2 B ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.40 (s, 1H),9.17 (d, J = 1.6 Hz, 1H), 9.13 (d, J = 1.6 Hz, 1H), 9.06 (s, 1H), 8.29(s, 1H), 7.08 (s, 1H), 6.71 (s, 1H), 6.48 (s, 2H), 2.79-2.75 (m, 3H),2.15-2.11 (m, 1H), 1.61-1.59 (m, 1H), 1.44-1.42 (m, 1H). 124

1.56 352.2 B ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.21 (s, 1H),8.15 (s, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.35(s, 2H), 4.70- 4.67 (m, 1H), 4.57-4.53 (m, 1H), 4.06- 4.03 (m, 1H),2.75-2.73 (m, 1H), 2.14- 2.10 (m, 1H), 1.60-1.58 (m, 1H), 1.42- 1.38 (m,1H), 1.28 (d, J = 6.0 Hz, 3H). 125

1.52 343.1 B ¹HNMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.11 (s, 1H), 7.09(s, 1H), 6.92 (s, 1H), 4.98 (d, J = 3.6 Hz, 0.5H), 4.82- 4.81 (m, 0.5H),4.51 (d, J = 6.4 Hz, 1H), 2.72-2.61 (m, 1H), 2.59-2.53 (m, 1H),2.48-2.41 (m, 1H), 2.16-2.14 (m, 1H), 1.88-1.78 (m, 2H), 1.28-1.21 (m,4H). 126

1.65 370.2 B 1.65, [M + H]+ = 370.2, method = B. ¹HNMR (400 MHz,DMSO-d₆) δ 11.14 (s, 1H), 9.39 (s, 1H), 8.22 (s, 1H), 7.05 (d, J = 6.4Hz, 1H), 6.37 (s, 2H), 4.67 (t, J = 8.4 Hz, 1H), 4.54-4.52 (m, 1H), 4.06(t, J = 8.0 Hz, 1H), 2.77-2.76 (m, 1H), 2.14-2.12 (m, 1H), 1.60-1.56 (m,1H), 1.44-1.42 (m, 1H), 1.15 (d, J = 6.0 Hz, 3H). 127

1.52 352.1 B 1.52, [M + H]+ = 352.1. method = B. ¹HNMR (400 MHz,DMSO-d₆) δ 11.03 (s, 1H), 9.20 (s, 1H), 8.15 (s, 1H), 7.00 (d, J = 1.6Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.35 (s, 2H), 4.70-4.67 (m, 1H),4.57-5.54 (m, 1H), 4.06-4.03 (m, 1H), 2.75-2.72 (m, 1H), 2.14-2.10 (m,1H), 1.60-1.55 (m, 1H), 1.44-1.40 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H). 128

1.47 345.1 B ¹HNMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 9.19 (s, 1H),8.19 (s, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.93 (s, 1H), 6.32 (s, 2H),5.02-5.00 (m, 0.5H), 4.84-4.83 (m, 0.5H), 4.72-4.67 (m, 1H), 4.58- 4.54(m, 1H), 4.06-4.03 (m, 1H), 2.26- 2.23 (m, 1H), 1.69-1.63 (m, 1H), 1.28(d, J = 6.4 Hz, 3H), 1.17-1.13 (m, 1H). 130

1.698 350.1 C ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 9.33 (s, 1H),8.81 (d, J = 0.4 Hz, 1H), 8.29 (s, 1H), 7.20 (s, 1H), 6.97 (d, J = 1.2Hz, 1H), 6.37 (s, 2H), 2.78-2.73 (m, 1H), 2.42 (s, 3H), 2.16- 2.12 (m,1H), 1.62-1.57 (m, 1H), 1.46- 1.41 (m, 1H). 131

1.396 352.1 C ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.20 (s, 1H),8.14 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.315(s, 2H), 5.78-5.77 (m, 1H), 4.34-4.28 (m, 1H), 3.82-3.71 (m, 1H),2.77-2.72 (m, 1H), 2.44-2.33 (m, 1H), 2.15-2.10 (m, 1H), 1.87-1.82 (m,1H), 1.60-1.56 (m, 1H), 1.44- 1.40 (m, 1H). 132

1.394 352.1 C ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.20 (s, 1H),8.14 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.33(s, 2H), 5.79-5.78 (m, 1H), 4.34-4.28 (m, 1H), 3.79-3.71 (m, 1H),2.75-2.73 (m, 1H), 2.42-2.39 (m, 1H), 2.13-2.10 (m, 1H), 1.87-1.82 (m,1H), 1.61-1.56 (m, 1H), 1.44-1.41 (m, 1H). 133

1.72 375.2 F ¹HNMR (400 MHz, CD₃OD) δ 9.19 (s, 1H), 8.23 (s, 1H), 7.45(s, 1H), 6.96 (s, 1H), 6.73 (d, J = 1.6 Hz, 1H), 3.95 (s, 3H), 3.47-3.40(m, 1H), 2.67-2.62 (m, 1H), 2.15-2.10 (m, 1H), 1.62-1.52 (m, 2H), 1.36(d, J = 6.8 Hz, 6H). 134

1.83 386.1 B ¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.38 (s, 1H),8.28 (s, 1H), 7.46 (s, 1H), 7.25-7.22 (m, 3H), 7.16 (s, 1H), 6.82 (d, J= 1.2 Hz, 1H), 6.65-6.64 (m, 2H), 2.78-2.76 (m, 1H), 2.17-2.12 (m, 1H),1.62-1.58 (m, 1H), 1.46-1.41 (m, 1H). 135

1.40 326.1 E ¹H NMR (400 MHz, CD₃OD) δ 9.25 (s, 1H), 8.47 (d, J = 5.6Hz, 1H), 8.41 (s, 1H), 7.53 (s, 1H), 7.40 (d, J = 5.2 Hz, 1H), 6.91 (d,J = 6.0 Hz, 1H), 2.91 (s, 3H), 2.31 (s, 3H). 136

1.67 400.1 C ¹H NMR (400 MHz, CD₃OD): δ 9.24 (s, 1H), 8.27 (s, 1H),7.75-7.73 (m, 2H), 7.40-7.38 (m, 1H), 6.97 (s, 1H), 6.71 (s, 1H), 2.92(s, 3H), 2.67-2.62 (m, 1H), 2.34 (s, 3H), 2.14-2.09 (m, 1H), 1.62-1.52(m, 2H). 138

1.77 399.1 C ¹H NMR (400 MHz, DMSO-d₆): δ 11.15 (s, 1H), 9.35 (s, 1H),8.26 (s, 1H), 7.27-7.08 (m, 5H), 6.78 (s, 1H), 6.54 (s, 2H), 3.17 (s,3H), 2.77-2.74 (m, 1H), 2.17-2.12 (m, 1H), 1.62-1.57 (m, 1H), 1.46-1.41(m, 1H). 139

1.47 319.7 C ¹HNMR (400 MHz, DMSO-d₆): δ 13.01 (s, 1H), 11.02 (s, 1H),9.21 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.19 (s, 1H),6.86 (s, 1H), 6.17 (s, 2H), 2.77-2.74 (m, 1H), 2.15-2.11 (m, 1H),1.61-1.56 (m, 1H), 1.46-1.41 (m, 1H). 140

1.64 385.1 C ¹HNMR (400 MHz, DMSO-d₆): δ 11.13 (s, 1H), 9.34 (s, 1H),8.25 (s, 1H), 7.15-7.00 (m, 6H), 6.79 (s, 1H), 6.51 (s, 2H), 2.78-2.74(m, 1H), 2.17- 2.12 (m, 1H), 1.61-1.57 (m, 1H), 1.46- 1.41 (m, 1H). 143

1.864 421.1 C 1.864, [M + H]⁺ = 421.1, Method = C; ¹HNMR (400 MHz,CD₃OD): δ 9.41 (s, 1H), 8.39 (s, 1H), 8.25-8.23 (m, 2H), 7.35 (s, 1H),6.74 (s, 1H), 2.64- 2.26 (m, 1H), 2.16 (s, 3H), 2.09-2.05 (m, 1H),1.57-1.47 (m, 2H). 144

1.332 351.2 A ¹HNMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 9.11 (s, 1H),8.08 (s, 1H), 7.36 (s, 1H), 7.25 (s, 1H), 6.71 (s, 1H), 6.18 (s, 2H),4.12-3.97 (m, 2H), 3.81-3.75 (m, 1H), 2.76-2.67 (m, 1H), 2.14-2.08 (m,1H), 1.58-1.50 (m, 1H), 1.42-1.40 (m, 1H), 1.20 (d, J = 6.0 Hz, 3H). 145

1.625 380.2 G ¹H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.53 (s, 1H),8.55 (d, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.48 (d, J = 5.2Hz, 1H), 6.20 (s, 2H), 2.62-2.75 (m, 1H), 2.11-2.25 (m, 4H), 1.60-1.68(m, 1H), 1.40-1.48 (m, 1H). 146

1.667 378.1 G ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.36 (d, J = 5.2 Hz, 1H), 6.96 (s,1H), 6.61 (s, 1H), 6.03 (br, 2H), 2.79-2.71 (m, 1H), 2.17- 2.10 (m, 1H),2.11 (s, 3H), 1.63-1.55 (m, 1H), 1.46-1.40 (m, 1H). 147

1.533 342.2 G ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 9.12 (s, 1H),8.48 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.36 (d, J = 5.2Hz, 1H), 7.04 (q, J = 4.8 Hz, 1H), 6.85 (s, 1H), 6.52 (s, 2H), 2.71 (d,7 = 4.8 Hz, 3H), 2.12 (s, 3H). 148

1.499 342.1 G 1.499, [M + H]⁺ = 342.1, method = G; ¹H NMR (400 MHz,DMSO-d6) δ 9.28 (s, 1H), 9.23 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.32(s, 1H), 8.22 (s, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.06 (q, J = 4.8 Hz,1H), 6.49 (s, 2H), 6.36 (s, 1H), 2.72 (d, J = 4.8 Hz, 3H), 2.12 (s, 3H).149

1.512 333.1 C ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 9.32 (s, 1H),8.51 (d, J = 5.2 Hz, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.39 (d, J = 5.2Hz, 1H), 7.35 (s, 2H), 7.07 (q, J = 4.4 Hz, 1H), 6.80 (s, 1H), 2.71 (d,J = 4.4 Hz, 3H), 2.22 (s, 3H). 150

1.428 333.2 G ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 9.34 (s, 1H),8.54 (d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.50 (s, 2H), 7.43(d, J = 5.2 Hz, 1H), 7.00 (q, J = 4.4 Hz, 1H), 6.41 (s, 1H), 2.73 (d, J= 4.4 Hz, 3H), 2.22 (s. 3H). 151

1.398 338.0 C ¹H NMR (400 MHz, CD₃OD) δ 9.20 (s, 1H), 8.27 (s, 1H), 7.06(s, 1H), 6.74 (s, 1H), 5.72-5.68 (m, 1H), 4.07-4.02 (m, 1H), 3.53-3.49(m, 1H), 2.65-2.62 (m, 1H), 2.13-2.11 (m, 1H), 1.61-1.53 (m, 1H). 153

1.852 374.1 C ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 9.46 (s, 1H),8.46 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.19 (s, 1H), 7.34(d, J = 4.8 Hz, 1H), 6.75 (s, 1H), 6.32 (s, 2H), 4.95 (s, 1H), 4.29 (d,J = 12.4 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H), 2.78-2.75 (m, 1H), 2.17-2.11 (m, 1H), 2.08 (s, 3H), 1.61-1.56 (m, 1H), 1.46-1.40 (m, 1H). 154

1.399 344.2 A ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.80 (s, 1H),7.67 (s, 1H), 7.21 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H), 6.84(s, 1H), 6.25 (s, 2H), 4.71-4.68 (m, 1H), 4.55 (t, J = 8.2 Hz, 1H), 4.04(q, J = 4.4 Hz, 1H), 3.84- 3.78 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H), 1.13(d. 7 = 6.8 Hz, 6H). 155

1.59 373.1 C ¹H NMR (400 MHz, DMSO-d₆): 12.62 (s, 1H), 10.52 (s, 1H),9.31 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.65(s, 1H), 7.39 (d, J = 5.2 Hz, 1H), 6.88 (s, 1H), 6.35 (d, J = 6.8 Hz,1H), 6.34 (s, 2H), 6.22 (d, J = 6.8 Hz, 1H), 3.83 (s, 2H), 2.64 (q, J =7.6 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). 156

1.49 359.1 C ¹H NMR (400 MHz, CD₃OD): 9.25 (s, 1H), 8.28 (s, 2H), 7.97(s, 1H), 7.74 (s, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 2.66- 2.64 (m, 1H),2.14 (s, 3H), 2.14- 2.11 (m, 1H), 1.62-1.54 (m, 2H). 157

1.80 468.1 C ¹H NMR (400 MHz, CD₃OD): 9.25 (s, 1H), 8.28 (s, 1H), 7.82(s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.97 (s,1H), 4.17-4.10 (m, 2H), 2.67-2.62 (m, 1H), 2.36 (s, 3H), 2.14- 2.09 (m,1H), 1.62-1.52 (m, 2H). 159

1.572 350.1 C ¹H NMR (400 MHz, CD₃OD): δ 9.26 (s, 1H), 8.33 (s, 1H),7.02 (s, 1H), 6.65 (s, 1H), 4.65 (s, 1H), 2.67-2.62 (m, 1H), 2.15-2.09(m, 1H), 2.01 (s, 3H), 1.62-1.52 (m, 2H). 160

1.35 365.1 C ¹HNMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 9.27 (s, 1H),8.16 (s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 6.30 (s, 2H), 4.05-3.92 (m,2H), 3.17-3.12 (m, 2H), 2.78-2.74 (m, 3H), 2.17-2.11 (m, 1H), 1.61-1.56(m, 1H), 1.45-1.42 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H). 161

1.65 370.1 B ¹HNMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.39 (s, 1H),8.22 (s, 1H), 7.06 (d, J = 6.4 Hz, 1H), 6.39 (s, 2H), 4.67 (t, J = 8.0Hz, 1H), 4.53 (d, J = 7.2 Hz, 1H), 4.06 (t, J = 8.0 Hz, 1H), 2.75-2.71(m, 1H), 2.15-2.12 (m, 1H), 1.61-1.57 (m, 1H), 1.42-1.40 (m, 1H), 1.15(d, J = 6.0 Hz, 3H). 162

3.83 400.1 J n/a 163

3.83 400.1 J n/a 164

1.50 345.2 B ¹HNMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 9.19 (s, 1H), 8.19(s, 1H), 7.0 (s, 1H), 6.93 (s, 1H), 4.84-5.02 (m, 1H), 4.58-4.72 (m,1H), 4.56 (t, 1H), 4.04-4.07 (m, 1H), 2.23-2.51 (m, 1H), 1.63-1.70 (m,1H), 1.14-1.3 (m, 4H) 165

1.52 345.2 B n/a 166

2.48 359.1 J ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.32 (s, 1H),8.21 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 6.82 (s, 1H), 6.53 (s, 1H),6.31 (s, 2H), 5.18 (s, 1H), 2.73-2.77 (m, 1H), 2.12-2.14 (m, 1H),1.59-1.61 (m, 1H), 1.40-1.57 (m, 1H) 167

2.48 359.1 J ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.31 (s, 1H),8.21 (s, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 6.82 (s, 1H), 6.53 (s, 1H),6.31 (s, 2H), 5.18 (s, 1H), 2.73-2.77 (m, 1H), 2.12-2.14 (m, 1H),1.59-1.61 (m, 1H), 1.40-1.57 (m, 1H) 168

4.66 350.1 J ¹H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 3.34 (s, 1H),8.48 (s, H), 8.29 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 6.55 (s, 2H),2.74-2.76 (m, 1H), 2.40 (s, 3H), 2.08-2.17 (m, 1H), 1.62-1.63 (m, 1H),1.40-1.45 (m, 1H) 169

4.66 350.1 J ¹H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 3.34 (s, 1H),8.48 (s, H), 8.29 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 6.55 (s, 2H),2.74-2.76 (m, 1H), 2.40 (s, 3H), 2.08-2.17 (m, 1H), 1.62-1.58 (m, 1H),1.40-1.45 (m, 1H) 170

2.76 383.1 J 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.34 (s, 1H), 8.86(s, 1H), 8.29 (d, J = 9.8 Hz, 2H), 7.66 (d, J = 3.1 Hz, 1H), 7.22 (s,1H), 7.00 (d, J = 1.5 Hz, 1H), 6.68 (dd, J = 3.0, 0.8 Hz, 1H), 6.37 (s,2H), 3.97 (s, 3H), 2.80-2.73 (m, 1H), 2.17-2.11 (m, 1H), 1.63- 1.55 (m,1H), 1.48-1.40 (m, 1H) 171

3.09 384.1 J 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.36 (s, 1H), 9.20(s, 1H), 8.47 (s, 1H), 8.40-8.29 (m, 2H), 7.34 (s, 1H), 7.06 (d, J = 1.5Hz, 1H), 6.44 (s, 2H), 4.24 (s, 3H), 2.77 (dd, J = 10.8, 8.0 Hz, 1H),2.19-2.09 (m, 1H), 1.65- 1.56 (m, 1H), 1.49-1.39 (m, 1H) 172

2.70 384.1 J 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.35 (s, 1H), 9.15(s, 1H), 8.76 (s, 1H), 8.32 (d, J = 14.3 Hz, 2H), 7.33 (s, 1H), 7.02 (d,J = 1.5 Hz, 1H), 6.39 (s, 2H), 4.30 (s, 3H), 2.75 (d, J = 5.9 Hz, 1H),2.19-2.09 (m, 1H), 1.64- 1.55 (m, 1H), 1.49-1.39 (m, 1H) 173

3.58 366.1 J 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.19 (s, 1H), 8.12(s, 1H), 7.21 (d, J = 2.1 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.34 (s,2H), 3.89 (s, 2H), 2.74 (dd, J = 11.4, 7.2 Hz, 1H), 2.18-2.09 (m, 1H),1.60-1.55 (m, 1H), 1.48 (s, 6H), 1.42 (dt, J = 10.2, 5.1 Hz, 1H). 174

3.89 380.1 J 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.21 (s, 1H), 8.15(s, 1H), 7.00 (s, 2H), 6.35 (s, 2H), 4.63 (dd, J = 8.4, 4.1 Hz, 1H),4.42 (t, J = 8.9 Hz, 1H), 4.29 (dd, J = 9.0, 4.0 Hz, 1H), 2.73 (d, J =12.9 Hz, 1H), 2.16-2.07 (m, 2H), 1.61-1.55 (m, 1H), 1.42 (dt, J = 9.3,4.7 Hz, 1H), 0.88 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H). 175

3.98 380.2 J 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.21 (s, 1H), 8.15(s, 1H), 7.00 (s, 2H), 6.35 (s, 2H), 4.69-4.59 (m, 1H), 4.42 (t, J = 8.9Hz, 1H), 4.30 (dd, J = 8.9, 4.0 Hz, 1H), 2.79-2.69 (m, 1H), 2.18-2.06(m, 2H), 1.64-1.54 (m, 1H), 1.46-1.37 (m, 1H), 0.88 (d, J = 7.0 Hz, 3H),0.75 (d, J = 6.8 Hz, 3H). 176

3.02 338.1 J 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.19 (s, 1H), 8.14(s, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 6.35 (s,2H), 4.47-4.40 (m, 2H), 4.13-4.06 (m, 2H), 2.78-2.71 (m, 1H), 2.17-2.08(m, 1H), 1.61-1.54 (m, 1H), 1.46-1.38 (m, 1H). 177

3.73 378.1 J 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.19 (s, 1H), 8.14(s, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 1.8 Hz, 1H), 6.35 (s,2H), 5.14-5.04 (m, 1H), 4.89 (s, 1H), 2.73 (d, J = 5.3 Hz, 1H),2.16-2.08 (m, 1H), 2.01-1.93 (m, 1H), 1.86-1.76 (m, 3H), 1.68 (s, 1H),1.63-1.52 (m, 2H), 1.42 (d, J = 4.3 Hz, 1H). 178

3.32 378.1 N* 179

3.39 360.1 N* 180

1.23 479 K ¹HNMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.56 (d, J =5.1 Hz,1H), 8.20 (s, 1H), 7.49 (d, J = 5.7 Hz, 2H), 7.37 (s, 1H), 7.20 (d, J =2.0 Hz, 1H), 6.82 (s, 1H), 6.47 (d, J = 1.3 Hz, 1H), 5.99 (d, J = 2.0Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.38-2.33 (m, 1H), 2.29 (s, 3H),2.12-2.04 (m, 1H), 1.57-1.53 (m, 1H), 1.30-1.18 (m, 1H). 181

1.22 479 K ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.56 (d, J = 5.1 Hz,1H), 8.20 (s, 1H), 7.49 (d, J = 5.7 Hz, 2H), 7.37 (s, 1H), 7.20 (d, J =2.0 Hz, 1H), 6.82 (s, 1H), 6.47 (d, J = 1.3 Hz, 1H), 5.99 (d, J = 2.0Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.38-2.33 (m, 1H), 2.29 (s, 3H),2.12-2.04 (m, 1H), 1.57- 1.53 (m, 1H), 1.30-1.18 (m, 1H). 182

1.13 474 K ¹HNMR (300 MHz, CD₃OD) δ 9.14 (s, 1H), 8.47 (s, 1H), 8.13 (s,1H), 7.50 (s, 1H), 7.44-7.26 (m, 4H), 7.22-7.11 (m, 3H), 6.78 (s, 1H),6.50 (d, J = 1.3 Hz, 1H), 3.85 (d, J = 0.6 Hz, 3H), 2.41- 2.31 (m, 1H),2.27 (s, 3H), 2.13- 2.04 (m, 1H), 1.56-1.53 (m, 1H), 1.32- 1.17 (m, 1H).183

1.13 474, K ¹HNMR (300 MHz, CD₃OD) δ 9 14 (s, 1H), 8.47 (s, 1H), 8.13(s, 1H), 7.50 (s, 1H), 7.44-7.26 (m, 4H), 7.22-7.11 (m, 3H), 6.78 (s,1H), 6.50 (d, J = 1.3 Hz, 1H), 3.85 (s, 3H), 2.41-2.31 (m, 1H), 2.27 (s,3H), 2.13-2.04 (m, 1H), 1.56-1.53 (m, 1H), 1.32-1.17 (m, 1H). 184

2.02 482.3, K ¹HNMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 9.27 (s, 1H),8.24 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.56 (s, 1H), 7.29 (d, J = 0.8Hz, 1H), 6.94- 6.80 (m, 2H), 6.53 (d, J = 1.4 Hz, 1H), 6.20 (s, 2H),3.78 (s, 3H), 2.96 (s, 4H), 2.19 (t, J = 7.1 Hz, 2H), 2.07 (s, 3H), 1.36(qd, J = 7.0, 6.2, 4.3 Hz, 3H), 1.25 (d, J = 8.3 Hz, 4H), 1.20-1.10 (m,1H). 185

1.05 414.1, K ¹HNMR (300 MHz, DMSO-d₆) δ 10.75 (s, 1H), 9.30 (s, 1H),8.27 (s, 1H), 7.83 (d, J = 5.1 Hz, 1H), 7.57 (d, J = 0.9 Hz, 1H), 7.30(d, J = 0.8 Hz, 1H), 6.81 (d, J = 1.3 Hz, 1H), 6.53- 6.41 (m, 2H), 6.31(s, 2H), 5.78 (s, 2H), 3.78 (s, 3H), 2.20-2.16 (m, 2H), 1.98 (s, 3H),1.44-1.32 (m, 1H), 1.17- 1.14 (m, 1H). 186

1.03 401.1 K ¹HNMR (300 MHz, CD₃OD) δ 9.26 (s, 1H), 8.29 (s, 1H), 7.91(s, 1H), 7.76 (s, 1H), 6.97 (s, 1H), 6.68 (d, J = 1.4 Hz, 1H), 3.83-3.80(m, 1H), 2.71-2.60 (m, 1H), 2.18-2.03 (m, 4H), 1.58- 1.54 (m, 2H), 1.33(d, J = 12 Hz, 6H) 187

1.207 438.2 K ¹H NMR (300 MHz, CD₃OD) δ 9.28 (s, 1H), 8.41 (d, J = 5.1Hz, 1H), 8.23 (s, 1H), 7.35 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 7.15 (s,1H), 6.88 (s, 1H), 6.53 (s, 1H), 3.71 (s, 3H), 2.83-2.59 (m, 2H), 2.18(t, J = 0.7 Hz, 3H), 2.01 (dt, J = 8.7, 4.5 Hz, 1H), 1.85-1.58 (m, 1H),1.33 (dt, J = 9.0, 4.7 Hz, 1H), 1.07-1.00 (m, 1H). 188

1.193 346.1 K ¹HNMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H), 9.32 (s, 1H), 831 (s, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.11- 7.02 (m, 1H), 6.73 (d, J =1.5 Hz, 1H), 6.36 (s, 2H), 6.18 (s, 1H), 3.55-3.50 (m, 2H), 3.20-3.15(m, 2H), 2.06- 2.01 (m, 1H), 0.84-0.80 (m, 4H). 189

1.09 360.3 K ¹H NMR (300 MHz, CD₃OD) δ 9.21 (s, 1H), 8.28 (s, 1H), 7.94(s, 1H), 7.78 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 4.18- 3.91 (m,1H),3.34-3.31 (m, 1H), 2.81 (dd, J = 16.8 Hz, 7.7 Hz, 1H), 1.98-1.90 (m,1H), 1.29 (d, J = 6.2 Hz, 3H), 1.05-0.99 (m, 2H), 0.98- 0.85 (m, 2H).190

1.09 360.3 K ¹HNMR (300 MHz, CD₃OD) δ 9.21 (s, 1H), 8.28 (s, 1H), 7.94(s, 1H), 7.78 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 4.18- 3.91 (m, 1H),3.34-3.31 (m, 1H), 2.81 (dd, J = 16.8, 7.7 Hz, 1H), 1.98- 1.90 (m, 1H),1.29 (d, J = 6.2 Hz, 3H), 1.05-0.99 (m, 2H), 0.98-0.85 (m, 2H). 191

1.153 372.2 K ¹HNMR (400 MHz, DMSO-d₆) 10.80 (s, 1H), 9.32 (s, 1H),8.67-8.39 (m, 2H), 8.26 (s, 1H), 7.45 (d, J = 5.1 Hz, 1H), 6.97-6.81 (m,1H), 6.55 (d, J = 1.5 Hz, 1H), 6.37 (s, 2H), 2.81 (dd, J = 17.6, 7.3 Hz,1H), 2.69 (dd, J = 17.7, 7.7 Hz, 1H), 2.33 (s, 3H), 1.79 (t, J = 4.5 Hz,1H), 1.71-1.57 (m, 1H), 1.52- 1.37 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H).192

1.924 372.2 K ¹HNMR (400 MHz, DMSO-d₆) 10.79 (s, 1H), 9.32 (s, 1H),8.48-8.36 (m, 2H), 8.28 (s, 1H), 7.35 (d, J = 5.0 Hz, 1H), 6.99-6.86 (m,1H), 6.55 (d, J = 1.5 Hz, 1H), 6.34 (s, 2H), 2.83-2.61 (m, 2H), 2.30 (s,3H), 2.15-2.03 (m, 1H), 1.58-1.45 (m, 1H), 1.36 (dt, J = 9.1, 6.1 Hz,1H), 1.17 (d, J = 6.1 Hz, 3H). 193

1.08 388.2 K ¹HNMR (300 MHz, CD₃OD) δ 9.29 (s, 1H), 8.76 (s, 1H), 8.49(d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.62 (d, J= 0.8 Hz, 1H), 7.39- 7.34 (m, 1H), 6.83 (s, 1H), 6.76 (d, J = 6.1 Hz,1H), 6.13 (s, 2H), 5.82 (q, J = 7.1 Hz, 1H), 2.22 (s, 3H), 1.80 (d, J =7.1 Hz, 3H). 194

1.08 388.2 K ¹HNMR (300 MHz, CD₃OD) δ 9.29 (s, 1H), 8.76 (s, 1H), 8.49(d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.62 (d, J= 0.8 Hz, 1H), 7.39- 7.34 (m, 1H), 6 83 (s, 1H), 6.76 (d, J = 6.1 Hz,1H), 6.13 (s, 2H), 5.82 (q, J = 7.1 Hz, 1H), 2.22 (s, 3H), 1.80 (d, J =7.1 Hz, 3H). 195

1.14 461.3 K ¹HNMR (400 MHz, CD₃OD) δ 9.30 (s, 1H), 8.47 (d, J = 5.2 Hz,1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.45 (t, J = 6.2 Hz, 2H), 7.34 (s, 1H),7.00 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.34-2.32 (m, 4H), 2.17-2.14 (m,1H), 1.62-1.48 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H). 196

1.15 461.3 K ¹HNMR (400 MHz, CD₃OD) δ 9.31 (s, 1H), 8.46 (d, J = 5.2 Hz,1H), 8.41 (s, 1H), 8.34 (s, 1H), 7.51 (s, 1H), 7.42 (d, J = 5.2 Hz, 1H),7.39 (s, 1H), 6.98 (d, J = 6.0 Hz, 1H), 3.88 (s, 3H), 2.52-2.49 (m, 1H),2.30 (s, 3H), 1.99-1.97 (m, 1H), 1.79-1.72 (m, 1H), 1.17 (d, J = 6.4 Hz,3H). 197

1.15 461.3 K ¹HNMR (400 MHz, CD₃OD) δ 9.31 (s, 1H), 8.46 (d, J = 5.2 Hz,1H), 8.41 (s, 1H), 8.34 (s, 1H), 7.51 (s, 1H), 7.43 (d, J = 5.2 Hz, 1H),7.39 (s, 1H), 6.98 (d, J = 6.0 Hz, 1H), 3.88 (s, 3H), 2.53-2.49 (m, 1H),2.31 (s, 3H), 1.99-1.97 (m, 1H), 1.77-1.72 (m, 1H), 1.17 (d, J = 6.4 Hz,3H). 198

1.14 461.3 K ¹H NMR (400 MHz, CD₃OD) δ 9.30 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.45 (t, J = 6.2 Hz, 2H), 7.34 (s,1H), 7.00 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.34-2.32 (m, 4H),2.17-2.14 (m, 1H), 1.67-1.61 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H). 199

0.99 461.3 K ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.39 (d, J = 4.4Hz, 2H), 7.80 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 5.2 Hz,1H), 6.89 (s, 1H), 6.52 (s, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.59- 5.54(m, 1H), 2.39 (s, 3H), 1.91 (d, J = 6.8 Hz, 3H). 200

0.99 461.3 K ¹HNMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.39 (d, J = 4.4 Hz,2H), 7.80 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H),6.89 (s, 1H), 6.52 (s, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.59- 5.54 (m,1H), 2.39 (s, 3H), 1.91 (d, J = 6.8 Hz, 3H). 201

1.585 370.2 K ¹HNMR (300 MHz, CD₃OD) δ 9.12 (s, 1H), 8.39-8.37 (m, 2H),8.06 (s, 1H), 7.67 (s, 1H), 7.37 (d, J = 5.1 Hz, 1H), 6.82 (d, J = 5.1Hz, 2H), 6.45 (s, 1H), 5.62 (q, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.90 (d,J = 7.2 Hz, 3H) 202

0.946 370.2 K ¹HNMR (300 MHz, CD₃OD) δ 9.12 (s, 1H), 8.39-8.37 (m, 2H),8.06 (s, 1H), 7.67 (s, 1H), 7.37 (d, J = 5.1 Hz, 1H), 6.82 (d, J = 5.1Hz, 2H), 6.45 (s, 1H), 5.62 (q, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.90 (d,J = 7.2 Hz, 3H) 203

1.118 404.3 K ¹HNMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.42 (d, J = 5.1Hz, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.69 (s, 1H), 7.40 (d, J = 5.1 Hz,1H), 7.15 (s, 1H), 6.32 (s, 1H), 5.63 (q, J = 7.2, 1H), 2.22 (s, 3H),1.89 (d, J = 7.2, 3H) 204

2.202 438.1 K ¹HNMR (300 MHz, CD₃OD) δ 9.26 (s, 1H), 8.48 (d, J = 5.1Hz, 1H), 8.29 (s, 1H), 8.14 (1H, s), 7.70 (s, 1H), 7.46 (d, J = 5.1 Hz,1H), 7.16 (s, 1H), 5.65 (q, J = 7.2 Hz, 1H), 2.17 (s, 3H), 1.90 (d, J=7.2 Hz, 3H) 205

1.775 404.2 K ¹HNMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.42 (d, J = 5.1Hz, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.39 (d, J = 5.1 Hz,1H), 6.80 (s, 2H), 5.61 (q, J = 7.2 Hz, 1H), 2.22 (s, 3H), 1.89 (d, J =7.2 Hz, 3H) 206

1.777 404.2 K ¹HNMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.42 (d, J = 5.1Hz, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.39 (d, J = 5.1 Hz,1H), 6.80 (s, 2H), 5.61 (q, J = 7.2 Hz, 1H), 2.22 (s, 3H), 1.89 (d, J =7.2 Hz, 3H) 207

1.14 467.0 K ¹HNMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.24 (s, 1H), 7.93(d, J = 5.2 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.67-6.60(m, 2H), 3.86 (s, 3H), 3.15-3.07 (m, 4H), 2.42-2.32 (m, 1H), 2.15-2.04(m, 4H), 1.75-1.67 (m, 4H), 1.57 (dt, J = 9.1, 4.5 Hz, 1H), 1.33-1.20(m, 1H). 208

1.38 467.0 K ¹HNMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.24 (s, 1H), 7.93(d, J = 5.3 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.67-6.60(m, 2H), 3.86 (s, 3H), 3.15-3.07 (m, 4H), 2.37 (dt, J = 9.7, 4.4 Hz,1H), 2.14-2.04 (m, 4H), 1.75- 1.67 (m, 4H), 1.57 (dt, J = 9.3, 4.6 Hz,1H), 1.33-1.20 (m, 1H). 209

1.21 407.0 M ¹HNMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.45 (s, 1H),8.24 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 6.88 (s, 1H), 6.54 (s, 2H),5.22 (s, 2H), 2.77- 2.70 (m, 2H), 2.11-2.07 (m, 1H), 1.82 (s, 3H),1.58-1.55 (m, 1H), 1.15- 1.08 (m, 1H), 0.99-0.92 (m, 1H). 210

1.09 479.3 K ¹HNMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 8.41 (d, J =5.1 Hz,1H), 8.26 (s, 1H), 7.51 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27 (d, J=5.1 Hz, 1H), 7.16 (s, 1H), 6.89 (s, 1H), 6.53 (d, J = 1.4 Hz, 1H), 3.86(s, 3H), 3.71 (s, 3H), 2.36 (ddd, J = 9.6, 6.3. 4.0 Hz, 1H), 2.18 (s,3H), 2.14-2.05 (m, 1H), 1.56 (dt, J = 9.1, 4.6 Hz, 1H), 1.27-1.20 (m,1H). 211

1.09 479.3 K ¹HNMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 8.41 (d, J =5.1 Hz,1H), 8.26 (s, 1H), 7.51 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27 (d, J =5.1 Hz, 1H), 7.16 (s, 1H), 6.89 (s, 1H), 6.53 (d, J = 1.4 Hz, 1H), 3.86(s, 3H), 3.71 (s, 3H), 2.36 (ddd, J = 9.8, 6.4, 4.0 Hz, 1H), 2.18 (s,3H), 2.14-2.07 (m, 1H), 1.56 (dt, J = 9.2, 4.6 Hz, 1H), 1.28-1.19 (m,1H) 212

0.95 413.4 M ¹HNMR (300 MHz, CD₃OD) δ 9.26 (s, 1H), 8.45-8.43 (m, 2H),8.34 (s, 1H), 7.48 (s, 1H), 7.45 (d, J = 6.0 Hz 1H), 7.35 (s, 1H), 7.03(s, 1H), 6.70 (d, J = 3.0 Hz, 1H), 3.86 (s, 3H), 2.41 (s, 3H), 2.34 (dd,J = 6.5, 4.8 Hz, 1H), 2.17 (dd, J = 9.1, 4.9 Hz, 1H), 1.66 (dt, J = 8.9,6.2 Hz, 1H), 1.37 (d, J =6.2 Hz, 3H). 213

0.75 413.2 K ¹HNMR (400 MHz, CD₃OD) δ 9.26 (s, 1H), 8.46-8.37 (m, 2H),8.32 (s, 1H), 7.52 (s, 1H), 7.41 (d, J = 4.8 Hz, 2H), 7.04 (s, 1H), 6.69(d, J = 3.0 Hz, 1H), 3.89 (s, 3H), 2.52 (dd, J = 9.3, 4.7 Hz, 1H), 2.39(s, 3H), 1.99 (t, J = 4.7 Hz, 1H), 1.82-1.72 (m, 1H), 1.07 (d, J = 6.3Hz, 3H). 214

0.75 413.3 K ¹HNMR (300 MHz, CD₃OD) δ 9.24 (s, 1H), 8.42 (d, J = 5.4 Hz,2H), 8.33 (s, 1H), 7.53 (s, 1H), 7.41 (t, J = 2.6 Hz, 2H), 7.01 (s, 1H),6.70 (d, J = 3.0 Hz, 1H), 3.90 (s, 3H), 2.53 (dd, J = 9.2, 4.7 Hz, 1H),2.39 (s, 3H), 2.00 (t, J = 4.7 Hz, 1H), 1.77 (ddd, J = 9.4, 6.1, 4.7 Hz,1H), 1.07 (d, J = 6.2 Hz, 3H). 215

0.95 413.3 N ¹HNMR (300 MHz, CD₃OD) δ 9.31 (s, 1H), 8.49-8.39 (m, 2H),8.34 (s, 1H), 7.55-7.41 (m, 2H), 7.35 (s, 1H), 7.03 (s, 1H), 6.70 (d, J= 3.0 Hz, 1H), 3.86 (s, 3H), 2.41 (s, 3H), 2.34 (dd, J = 6.5, 4.9 Hz,1H), 2.17 (dd, J = 9.1, 4.9 Hz, 1H), 1.66 (dt, J = 9.0, 6.3 Hz, 1H),1.37 (d, J = 6.2 Hz, 3H) 216

1.30 452.1 K ¹HNMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.32 (s, 1H),8.26 (s, 1H), 7.63-7.55 (m, 3H), 7.48-7.41 (m, 1H), 7.29 (s, 1H), 6.79(s, 1H), 6.40 (s, 1H), 6.35 (s, 2H), 3.77 (s, 3H), 2.21-2.16 (m, 2H),1.39-1.35 (m, 1H), 1.19-1.14 (m, 1H). 217

1.31 452.2 K ¹HNMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.32 (s, 1H),8.26 (s, 1H), 7.65- 7.51 (m, 3H), 7.46 (dd, J = 8.7, 7.5 Hz, 1H), 7.30(s, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 6.35 (s, 2H), 3.78 (s, 3H),2.23-2.13 (m, 2H), 1.42-1.33 (m, 1H), 1.21-1.12 (m, 1H). 218

1.49 420.2 K ¹HNMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 8.30 (s, 1H), 7.51(s, 1H), 7.44 (ddd, J = 8.5, 6.3, 2.1 Hz, 1H), 7.38 (s, 1H), 7.10 (t, J= 8.0 Hz, 3H), 6.78 (s, 1H), 3.86 (s, 3H), 2.37 (td, J = 6.1, 3.2 Hz,1H), 2.11 (dt, J = 8.7, 4.7 Hz, 1H), 1.57 (ddd, J = 9.2, 5.1, 4.1 Hz,1H), 1.26 (ddd, J = 8.2, 6.4, 4.1 Hz, 1H). 219

1.49 420.2 K ¹HNMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 8.30 (s, 1H), 7.51(s, 1H), 7.44 (ddd, J = 8.5, 6.3, 2.1 Hz, 1H), 7.38 (s, 1H), 7.10 (t, J= 8.0 Hz, 3H), 6.78 (s, 1H), 3.86 (s, 3H), 2.37 (td, J = 6.1, 3.2 Hz,1H), 2.11 (dt, J = 8.7, 4.7 Hz, 1H), 1.57 (ddd, J = 9.2, 5.1, 4.1 Hz,1H), 1.26 (ddd, J = 8.2, 6.4, 4.1 Hz, 1H). 220

1.55 368.2 M ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.37 (s, 1H),8.24 (s, 1H), 7.76 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 7.50(t, J = 5.8 Hz, 1H), 6.86 (s, 1H), 6.46 (d, J = 7.2 Hz, 3H), 2.78-2.72(m, 1H), 2.16-2.10 (m, 4H), 1.62-1.57 (m, 1H), 1.45- 1.43 (m, 1H). 221

1.55 368.2 M ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.37 (s, 1H),8.24 (s, 1H), 7.76 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 7.50(t, J = 5.8 Hz, 1H), 6.86 (s, 1H), 6.46 (d, J = 7.2 Hz, 3H), 2.78-2.72(m, 1H), 2.16-2.10 (m, 4H), 1.62-1.57 (m, 1H), 1.45- 1.43 (m, 1H). 222

1.10 479.3 K ¹HNMR (400 MHz, DMSO-d₆) 10.74 (s, 1H), 9.27 (s, 1H), 8.48(d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.56 (s, 1H), 7.38-7.29 (m, 3H), 6.71(s, 1H), 6.33 (s, 1H), 6.20 (s, 2H), 5.77 (s, 1H), 3.77 (s, 3H), 3.68(s, 3H), 2.18 (t, J = 6.0 Hz, 2H), 2.09 (s, 3H), 1.35-1.34 (m, 1H),1.17- 1.15 (m, 1H). 223

1.10 479.3 K ¹HNMR (400 MHz, DMSO-d₆) 10.74 (s, 1H), 9.27 (s, 1H), 8.48(d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.56 (s, 1H), 7.38-7.29 (m, 3H), 6.71(s, 1H), 6.33 (s, 1H), 6.20 (s, 2H), 5.77 (s, 1H), 3.77 (s, 3H), 3.68(s, 3H), 2.18 (t, J = 6.0 Hz, 2H), 2.09 (s, 3H), 1.35-1.34 (m, 1H),1.17-1.15 (m, 1H). 224

2.236 409.1 K ¹HNMR (300 MHz, DMSO-d₆) 10.59 (s, 1H), 9.44 (s, 1H), 8.49(d, J = 6.0 Hz, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.37 (d, J = 6.0 Hz,1H), 6.91 (s, 1H), 6.57 (s, 2H), 4.70 (d, J = 6.0 Hz, 1H), 3.85-3.78 (m,1H), 2.11 (s, 3H), 2.09- 2.04 (m, 2H), 1.89-1.87 (m, 1H), 1.73-1.71 (m,2H), 1.69-1.61 (m, 2H). 225

1.029 409.2 K ¹HNMR (300 MHz, DMSO-d₆) 10.70 (s, 1H), 9.37 (s, 1H), 8.62(s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.32 (s, 1H), 7.38 (d, J = 6.0 Hz,1H), 6.54 (s, 2H), 6.44 (s, 1H), 4.71 (d,. J = 6.0 Hz, 1H), 3.83- 3.78(m, 1H), 2.12 (s, 3H), 2.09-2.05 (m, 2H), 1.92-1.90 (m, 1H), 1.76- 1.74(m, 2H), 1.69-1.62 (m, 2H) 226

1.205 443.1 L ¹HNMR (300 MHz, DMSO-d₆) 10.79 (s, 1H), 9.53 (s, 1H), 8.64(s, 1H), 8.53 (d, J = 6.0 Hz, 1H), 8.29 (s, 1H), 7.43 (d, J = 6.0 Hz,1H), 6.77 (s, 2H), 4.71 (d, J = 6.0 Hz, 1H), 3.85-3.79 (m, 1H),2.12-2.08 (m, 2H), 2.05 (s, 3H), 1.92-1.90 (m, 1H), 1.75-1.74 (m, 2H),1.69-1.62 (m, 2H) 227

1.006 446.3 L n/a 228

458.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.02 (s, 1H), 8.51 (d, J= 6.0 Hz, 1H), 8.43 (s, 1H), 7.68 (s, 1H), 7.39 (d, J = 6.0 Hz, 1H),6.79 (d, J = 6.0 Hz, 1H), 6.11 (s, 2H), 5.61 (s, 1H), 5.06 (s, 2H), 3.73(s, 2H), 2.99 (s, 3H), 2.22 (s, 3H), 1.24-1.18 (m, 2H). 0.96- 0.94 (m,2H). 229

0.942 447.2 L ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.07 (s, 1H),7.99 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 6.72 (d, J = 6.1 Hz, 1H), 6.07(s, 2H), 5.99 (s, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 3.84 (t, J = 5.7 Hz,2H), 3.05 (t, J = 5.6 Hz, 2H), 2.96 (s, 3H), 1.94 (d, J = 1.5 Hz, 3H).230

0.957 432.3 L ¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.11 (s, 1H),8.51 (s, 1H), 8.43 (s, 1H), 7.74 (s, 1H), 7.39 (d, J = 7.2 Hz, 1H), 6.78(d, J = 7.2 Hz, 1H), 6.13 (s, 2H), 5.98 (s, 1H), 4.97 (s, 2H), 3.84-3.81(m, 2H), 3.05-3.03 (m, 2H), 2.95 (s, 3H), 2.22 (s, 3H).

TABLE A-4 LCMS R_(T) (min); Cmpd M + H⁺; No. Structure/Name Method 9

See Example 134(1R,2S,3R)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;ethyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 10

See Example 134(1S,2R,3S)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;ethyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 11

See Example 134(1S,2S,3S)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;ethyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 12

See Example 134(1R,2R,3R)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;ethyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 29

See Example 1331-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(cyclopropylmethyl)urea 33

See Example 135(1S,2S,3S)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;methyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 34

See Example 135(1R,2R,3R)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;methyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 35

See Example 135(1S,2R,3S)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;methyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 36

See Example 135(1R,2S,3R)-N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide;methyl relative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 53

2.71 412.1 N tetrahydro-2H-pyran-4-yl(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)carbamate 58

2.54 386.1 N 2-methoxyethyl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinoin-3-yl)carbamate 64

2.50 352.1 NN-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)cyclopropanecarboxamide 83

2.53 377.1 N (1R,2R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide (Nitrile transto amide; Absolute stereochemistry arbitrarily assigned) 84

2.53 377.1 N (1S,2S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-cyanocyclopropane-1-carboxamide (Nitrile transto amide; Absolute stereochemistry arbitrarily assigned) 96

1.39 326.12 K7-Fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinoline-3,8-diamine 97

1.45 2.76.1 E3,8-diamino-6-(4-methylpyridin-3-yl)isoquinoline-7-carbonitrile 111

See Example 137(R)-1-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea (Absolute stereochemistry arbitrarily assigned) 112

See Example 137(S)-1-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea (Absolute stereochemistry arbitrarily assigned) 114

3.05 382.1 N cyclopropylmethyl(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)carbamate 120

See Example 173 (1S,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Absolutestereochemistry arbitrarily assigned) 121

See Example 173 (1R,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2,2-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Absolutestereochemistry arbitrarily assigned) 129

2.91 370.1 N isopropyl (8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)carbamate 137

2.78 379.1 N1-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-3-(1-cyanopropan-2-yl)urea 141

2.42 430.1 N (+/−)-7-fluoro-6-(4-methylpyridin-3-yl)-N3-(3-(morpholin-3-yl)phenyl)isoquinoline-3,8-diamine 142

2.42 430.1 N (S)-7-fluoro-6-(4-methylpyridin-3-yl)-N3-(3-(morpholin-3-yl)phenyl)isoquinoline-3,8-diamine 152

See Example 229(+/−)-cis-N-(8-amino-6-(2,6-dichlorophenyl)-7-fluoroisoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide 158

2.53 394.1 N (1R,5S,6r)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 231

See Example 1912-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(methyl-d3)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 232

See Example 2302-((6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 233

See Example 1362-((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 234

See Example 1382-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,5-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 235

See Example 1392-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,5,6-trimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 236

See Example 140(1S,2S,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyl trans to amide; methyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarily assigned)237

See Example 140(1R,2R,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyl trans to amide; methyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarily assigned)238

See Example 140(1R,2R,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyl trans to amide; methyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarily assigned)239

See Example 140(1S,2S,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyl trans to amide; methyl relative stereochemistryarbitrarily assigned; All absolute stereochemistry arbitrarily assigned)240

See Example 141 2-((8-amino-7-fluoro-6-((2-oxo-1,2-dihydropyridin-3-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 241

See Example 142N-(8-amino-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)ethanesulfonamide 242

See Example 1435-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-ethyloxazol-2(3H)-one 243

See Example 1442-((8-amino-6-(5-amino-4-chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 244

See Example 145 2-((8-amino-7-fluoro-6-((4-methyl-2-oxopiperazin-1-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 245

See Example 1465-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-N,N,4-trimethylpyrimidine-2-carboxamide 246

See Example 1472-((8-amino-6-(5-amino-4-methoxypyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 247

See Example 1486-(5-amino-4-methylpyridin-3-yl)-N3-(5,6-dihydro-11H-imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8-yl)-7-fluoroisoquinoline-3,8-diamine248

4.13 423.2 N2-((8-amino-7-fluoro-6-(2-methylprop-1-en-1-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 249

See Example 149 2-((6-((1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 250

See Example 1502-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-7-methyl-6,7-dihydro-5H-imidazo[1,2-d][1,4]diazepin-8(9H)-one 251

See Example 231 2-((8-amino-6-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 252

See Example 1512-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,5-dihydro-7H-pyrazolo[1,5-c][1,3]thiazine 6,6-dioxide 253

See Example 1522-((8-amino-6-cyclopropyl-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 254

See Example 1532-((8-amino-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 255

See Example 1542-((8-amino-7-fluoro-6-(2-isopropoxy-4-methylpyrimidin-5-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 256

See Example 1552-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-isopropyl-4,5-dihydro-7H-pyrazolo[5,1- d][1,2,5]thiadiazine6,6-dioxide 257

See Example 1562-((8-amino-6-(benzyloxy)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 258

See Example 1572-((8-amino-7-fluoro-6-methylisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 259

See Example 1582-((8-amino-7-fluoro-6-methoxyisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 260

See Example 1592-((8-amino-7-fluoro-6-((pyridin-2-yloxy)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 261

See Example 1602-((8-amino-7-fluoro-6-((2-oxopyridin-1(2H)-yl)methyl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 262

See Example 161(+/−)-6-(5-amino-4-methylpyridin-3-yl)-N3-(7,7-difluoro-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)-7-fluoroisoquinoline-3,8-diamine 263

See Example 1625-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-1-methyl-1,3-dihydroisothiazolo[4,3-b]pyridine 2,2-dioxide 264

2.88 388.2 N2-(8-amino-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)cyclopropane-1- carbonitrile265

See Example 1636-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4S,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Stereochemistry arbitrarily assigned) 266

See Example 1636-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4R,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Stereochemistry arbitrarily assigned) 267

See Example 1636-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4S,7R)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Stereochemistry arbitrarily assigned) 268

See Example 1636-(5-amino-4-methylpyridin-3-yl)-7-fluoro-N3-((4R,7S)-7-methoxy-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-2-yl)isoquinoline-3,8-diamine (Sterochemistry arbitrarily assigned) 269

See Example 1645-(8-amino-7-fluoro-3-((6-isopropyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-1-ethyl-1H-pyrazole-3-carbonitrile 270

See Example 1652-((8-amino-7-fluoro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 271

See Example 1662-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H,8H-pyrazolo[1,5-c][1,3]thiazepine 7,7- dioxide272

See Example 1672-((8-amino-7-fluoro-6-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 273

See Example 168.2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(2-hydroxy-2-methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 274

See Example 169 (R)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihdyro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolutestereochemistry arbitrarily assigned) 275

See Example 169 (S)-2-((8-amino-7-fluoro-6-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolutesterochemistry arbitrarily assigned) 276

See Example 1702-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-methyl-4,5-dihydro-7H-pyrazolo[5,1-d][1,2,5]thiadiazine6,6-dioxide 277

See Example 1712-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(oxetan-3-ylmethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 278

See Example 1722-((8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 279

See Example 173(1R,2R,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Ethyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 280

See Example 173(1S,2S,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Ethyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 281

See Example 173(1R,2S,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Ethyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 282

See Example 173(1S,2R,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Ethyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 283

See Example 1742-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-cyclopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 284

See Example 1752-((8-amino-6-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 285

2.78 422.2 N (+/−)-3-(8-amino-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-4-methyloxazolidin-2-one 286

See Example 1762-((8-amino-6-(5-amino-4-ethylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 287

See Example 177 (+/−)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-ethyl-4H,6H-pyrazolo[1,5-c]thiazole5,5-dioxide 288

See Example 1782-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(cyclopropylmethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 289

See Example 1792-((8-amino-7-fluoro-6-(5-hydroxy-4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 290

See Example 1802-((8-amino-7-fluoro-6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 291

See Example 1812-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2-methoxyethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 292

See Example 1822-((8-amino-7-fluoro-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 293

See Example 183 (+/−)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H,8H-pyrazolo[5,1-e][1,2,6]thiadiazepine 7,7-dioxide 294

4.25 476.2 N(1S,2S,3S)-N-(8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 295

4.27 476.2 N(1S,2R,3S)-N-(8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Methyl relativesterochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 296

4.27 476.2 N(1R,2S,3R)-N-(8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 297

4.25 476.2 N(1R,2R,3R)-N-(8-amino-6-(5-amino-6-methoxy-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazolel trans to amide; Methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 298

See Example 1842-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-ethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)- one299

See Example 1852-((8-amino-6-(5-amino-4,6-dimethylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 300

See Example 1862-((8-amino-6-(2-amino-3-methylpyridin-4-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6-dihdyro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 301

2.82 421.2 N2-((8-amino-7-fluoro-6-(5-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 302

See Example 1872-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-5-methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one 303

See Example 188(E)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-4-((1-methyl-1H-pyrazol-4-yl)methylene)-5,6-dihydro-4H-pyrazolo[1,5-d[[1,4]diazepin-7(8H)-one 304

2.82 421.2 N2-((8-amino-6-(3,5-dimethyl-1H-pyrazol-4-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 305

See Example 1892-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2,2-trifluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 306

See Example 1902-((8-amino-6-(5-amino-4-chloropyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 307

2.41 488.2 K 2-((8-amino-7-fluoro-6-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)isoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 308

See Examples 192 and 193(±)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 309

See Example 192 (R)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistryarbitrarily assigned) 310

See Example 193(S)-2-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-4-fluoro-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistry arbitrarilyassigned) 311

See Exmaple 194(+/−)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4-hydroxy-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 312

See Example 1952-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-(2,2-difluoroethyl)-5,6-dihdyro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 313

See Example 196(+/−)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4-hydroxy-4-(methoxymethyl)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 314

See Example 1972′-((8-amino-7-fluoro-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one 315

See Example 1982-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6-isopropyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 316

See Example 1992′-((8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)amino)-6′-methyl-5′,6′-dihydrospiro[cyclopropane-1,4′-pyrazolo[1,5-d][1,4]diazepin[-7′(8′H)-one 317

See Example 2002-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-methyl-4-methylene-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 318

See Example 201(+/−)-2-((8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 319

See Example 202(1R,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide (Imidazoletrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 320

See Example 202(1R,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide (Imidazoletrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 321

See Example 202(1S,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide (Imidazoletrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 322

See Example 202(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)-3-methylcyclopropane-1-carboxamide (Imidazoletrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 323

See Example 210(1R,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-(1H-imidazol-4-yl)cyclopropane-1- carboxamide(Relative stereochemistry as drawn; Absolute sterochemistry arbitrarilyassigned) 324

See Example 210(1S,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-(1H-imidazol-4-yl)cyclopropane-1- carboxamide(Relative stereochemistry as drawn; Absolute stereochemistry arbitrarilyassigned) 325

2.0 367.2 K(±)-cis-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide 326

See Example 205(1S,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide (Hydroxymethyl trans toamide; Absolute stereochemistry arbitrarily assigned) 327

See Example 204(1R,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide (Hydroxymethyl tran toamide; Absolute stereochmistry arbitrarily assigned) 328

See Example 203 (±)-(1R,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide 329

See Example 212(1R,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide (Pyrazoletran to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 330

See Example 212(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide (Pyrazoletrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 331

See Example 212(1S,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide (Pyrazoletran to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 332

See Example 212(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1H-pyrazol-5-yl)cyclopropane-1-carboxamide (Pyrazoletrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 333

1.30 403.2 K(±)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imdiazol-5-yl)cyclopropane-1-carboxamide 334

See Example 213(1R,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1-carboxamide (Relativestereochemistry as drawn; Absolute stereochemistry arbitrarily assigned)335

See Example 213(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-5-yl)cyclopropane-1-carboxamide (Relativestereochemistry as drawn; Absolute stereochemistry arbitrarily assigned)336

See Example 218N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-azabicyclo[2.1.1]hexane-2-carboxamide 337

See Example 214(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole tran to amide; methyl relative stereochemistryarbitrarily assigned; Absolute stereochemistry arbitrarily assigned) 338

See Example 214(1R,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; Absolute stereochemistry arbitrarily assigned) 339

See Example 214(1S,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyraozle trans to amide; methyl relative stereochemistryarbitrarily assigned; Absolute stereochemistry arbitrarily assigned) 340

See Example 214(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; Absolute sterochemistry arbitrarily assigned) 341

See Example 215(1S,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-((dimethylamino)methyl)cyclopropane-1-carboxamide (Relativestereochemistry as drawn; Absolute stereochemistry arbitrarily assigned)342

See Example 215(1R,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-((dimethylamino)methyl)cyclopropane-1-carboxamide (Relativestereochemistry as drawn; Absolute stereochemistry arbitrarily assigned)343

See Examples 208 and 209(±)-(1R,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide (Mixture of twoenantiomers with relative stereochemistry as drawn) 344

See Example 208(1R,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide (Single enantiomer with relative stereochemistry as drawn;Absolute stereochemistry arbitrarily assigned) 345

See Example 209(1S,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-((dimethylamino)methyl)cyclopropane-1-carboxamide (Single enantiomer with relative stereochemistry as drawn;Absolute stereochemistry arbitrarily assigned) 346

See Example 219(1R,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 347

See Example 219(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 348

See Example 219(1S,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 349

See Example 219(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 350

See Example 220(1R,2S,3R)-N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 351

See Example 220(1S,2R,3S)-N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 352

See Example 220(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 353

See Example 220(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methyl-6-(oxazol-2-yl)pyridin-3-yl)isoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 354

1.74 418.3 K(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(Relative stereochemistry as drawn; Absolute stereochemistry arbitrarilyassigned) 355

See Example 226(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(Relative stereochemistry as drawn; Absolute stereochemistry arbitrarilyassigned) 356

See Example 226(1R,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropane-1-carboxamide(Relative stereochemistry as drawn; Absolute stereochemistry arbitrarilyassigned) 357

See Example 222(1R,2R,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 358

See Example 222(1S,2S,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 359

See Example 222(1S,2R,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 360

See Example 222(1R,2S,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relativestereochemistry arbitrarily assigned; Absolute stereochemistryarbitrarily assigned) 361

See Example 223(S)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistry arbitrarily assigned) 362

See Example 223(R)-2-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-4,6-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one (Absolute stereochemistry arbitrarily assigned) 363

See Example 224(1S,2S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazol-5-yl)cyclopropane-1-carobxamide (Relativestereochemistry as drawn; Absolute stereochemistry arbitrarily assigned)364

See Example 224(1R,2R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-pyrazolo-5-yl)cyclopropane-1-carboxamide (Relativestereochemistry as drawn; Absolute stereochemistry arbitrarily assigned)365

See Example 225(1R,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; Absolute stereochemistry arbitrarily assigned) 366

See Example 225(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; Absolute steroechemistry arbitrarily assigned) 367

See Example 225(1S,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyraozle trans to amide; methyl relative stereochemistryarbitrarily assigned Absolute stereochemistry arbitrarily assigned) 368

See Example 225(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methyl relative stereochemistryarbitrarily assigned; Absolute stereochemistry arbitrarily assigned) 369

See Example 207(1S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; Absolute stereochemistryarbitrarily assigned) 370

See Example 207(1R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1H-imidazol-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Pyrazole trans to amide; Absolute stereochemistryarbitrarily assigned) 371

See Example 227 (1S,2R,6R,7S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide 372

See Example 227 (1R,2R,6S,7R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(Relative stereochemistry as drawn; All absolute stereochemistryarbitrarily assigned) 373

See Example 227 (1S,2R,6R,7S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(Relative stereochemistry as drawn; All absolute stereochemistryarbitrarily assigned) 374

See Example 227 (1R,2S,6S,7R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-hydroxybicyclo[4.1.0]heptane-7-carboxamide(Relative stereochemistry as drawn; All absolute stereochemistryarbitrarily assigned) 375

1.76, 460.2 K (1R,2S,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-imidazol-5-yl)cyclopropane-1-carboxamide (Imidazole trans to amide; ethyl relativestereochemistry arbitrarily assigned; All absolute stereochemistryarbitrarily assigned) 376

— 460.2 — (1S,2R,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-imidazol-5-yl)cyclopropane-1-carboxamide (Imidazole trans to amide; ethyl relativestereochemistry arbitrarily assigned; All absolute stereochemistryarbitrarily assigned) 377

— 460.2 — (1R,2R,3R)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-imidazol-5-yl)cyclopropane-1-carboxamide (Imidazole trans to amide; ethyl relativestereochemistry arbitrarily assigned; All absolute stereochemistryarbitrarily assigned) 378

— 460.2 — (1S,2S,3S)-N-(8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)-2-ethyl-3-(1-methyl-1H-imidazol-5-yl)cyclopropane-1-carboxamide (Imidazole trans to amide; ethyl relativestereochemistry arbitrarily assigned; All absolute stereochemistryarbitrarily assigned) 379

See Example 216(1S,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazeitidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methylrelative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 380

See Example 216(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methylrelative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 381

See Example 216(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyraozle trans to amide; methylrelative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 382

See Example 216(1R,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-3-methylcyclopropane-1-carboxamide (Pyrazole trans to amide; methylrelative stereochemistry arbitrarily assigned; All absolutestereochemistry arbitrarily assigned) 383

See Example 232(1S,2S,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyltrans to amide; methyl relative stereochemistry arbitrarily assigned;All absolute stereochemistry arbitrarily assigned) 384

See Example 232(1R,2R,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyltrans to amide; methyl relative stereochemistry arbitrarily assigned;All absolute stereochemistry arbitrarily assigned) 385

See Example 232(1S,2S,3S)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyltrans to amide; methyl relative stereochemistry arbitrarily assigned;All absolute stereochemistry arbitrarily assigned) 386

See Example 232(1R,2R,3R)-N-(8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)-2-(cyanomethyl)-3-methylcyclopropane-1-carboxamide (Cyanomethyltrans to amide; methyl relative stereochemistry arbitrarily assigned;Absolute stereochemistry arbitrarily assigned) 387

See Example 2062-((8-amino-7-fluoro-6-(4-methylpyridin-3-yl)isoquinolin-3-yl)amino)-6-(2,2,2-trifluoroethyl)-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 388

1.76 446.1 K2-((8-amino-6-(3-amino-2-methylphenyl)-7-fluoroisoquinolin-3-yl)amino)-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one 389

2.04 488.2 K6-(8-amino-7-fluoro-3-((6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino)isoquinolin-6-yl)-5-methylbenzo[d]oxazol-2(3H)-one 390

0.999 462.2 K2-((8-amino-6-(3-amino-2-methylphenyl)-7-fluoroisoquinolin-3-yl)amino)-4-hydroxy-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one

Biological Evaluation

Exemplary compounds of Formula I or Ia were tested to assess compoundinhibition of HPK-1. The K_(i) for each exemplary compound wasdetermined

Example B1 HPK1 Ki Determination Example B1A HPK1-FL HTRF EnzymaticAssay (“HTRF”)

Assay Principle:

HPK-FL enzyme phosphorylates Biotin-SLP-76 substrate in the presence ofATP at 1 mM and varying concentrations of test compound. Product isdetected by FRET using Eu-anti-pSLP76 Ab and SA-XL665. Also seewww.cisbio.com/HTRF for additional HTRF technology information.

Instrumentation:

Echo555 compound dispenser

Agilent Bravo

Perkin Elmer Envision

Final Assay Conditions:

HPK full length, 0.125 nM T165E S171E: Biotin-SLP76: 100 nM ATP: 1 mM(ATP Km = 20 μM) Eu-anti-pSLP76: 2 nM SA-XL665: 8.3 nM Preincubationtime: 30 min Kinase reaction time: 60 min Temperature: ambient Totalvolume: 12 μl ATP^(app) Km: 17.7 μM

Materials:

Assay plate: White ProxiPlate 384 F (PerkinElmer cat#6008289) Kinase:HPK full length double mutant Substrate: Biotin-SLP76 ATP: 100 mM ATPBSG: 2% BSG DMSO: DMSO (Sigma cat #34869-100ML) Reaction Buffer: H₂O/50mM HEPES, pH 7.5/10 mM MgCl₂/2 mM TCEP/0.01% Brij- 35/0.01% BSGDetection mix: Eu-anti-pSLP76/SA-XL665 (Cisbio, #610SAXAC)

Assay Procedure Ki Determination:

To a 384 well Proxiplate with 80 nL compound or DMSO spotted on wasadded 4 μl/well kinase mix. The mixture was preincubated for 30 minutesand then 4 μl/well substrate mix was added. The solution was incubatedfor 60 min and then 4 μl/well detection mix was added. The solution wasincubated for another 60 min. The plates were then loaded onto a PerkinElmer Envision and the TR-FRET signal was measured at 615 and 665 nm. Aratio of 665/620 was used to calculate the % activity at eachconcentration of compound.

Example B1B HPK1 Lantha Binding Assay (“Lanth”)

Materials:

Reagent Vender-Cat# white ProxiPlate PerkinElmer-6008289 384 F(assayplate) 384-well Microplate Labcyte-LP-0200 (compound plate) HPK1 enzymeSignalchem-M23-11G Tracer-222 Invitrogen-PV6121 Eu-Anti-GST AbInvitrogen-PV5594 Assay Buffer 2 mM DTT(Sigma-43815), 0.01%BRIJ-35(Sigma-B4184), 10 mM MgCl₂, 50 mM HEPES (Invitrogen-15630130)

Procedure: I. Compound Dilution:

The compounds to be tested were diluted by preparing 12.5 uL/well of 5mM compound (100×) in columns 2 and 13 and 10 ul/well of DMSO in columns3-12, 14-23, and wells A1-H1 and I24-P24 of the compound plate using aBravo liquid handling platform. For the reference compound, the topconcentration was 1 mM. To the plate was added 10 ul 2 mM staurosporinein wells J1-P1 and A24-H24. A 11 point 5-fold compound serial dilutionwas performed using the Bravo liquid handling platform. From the platewere transferred 2.5 ul of the solutions from column 2 and column 13 tothe 10 ul of DMSO in columns 3 and 14 & so on. The compound plate wascentrifuged at 2500 rpm for 1 min. From the compound plate wastransferred 80 nl of the compounds into an assay plate using the Echoliquid handler system. One compound plate makes two assay plates. Eachassay plate is sealed and stored in an N₂ cabinet.

II. Assay Condition:

The following assay concentrations and times were used: 2 nM HPK1, 2 nMEu-Anti-GST Ab, and 15 nM Tracer222, with 60 min incubation time.

III. HPK Lantha Binding Assay:

For the binding assay, 4 ul 2X HPK1 and Eu-anti-GST antibody were addedto each well of the assay plate using a Multidrop reagent dispenser. Thesolutions were incubated in a 23C incubator for 1 h. To each well of theassay plate was added 4 ul 2X Tracer-222 using a Multidrop reagentdispenser. The solutions were again incubated in a 23 C incubator for 1h. The results of the assay were read using an Envision plate readerwith the following parameters:TR_FRET, 340ex/615 and 665em; 100 usecDelay; and 200 usec integration.

IV. Analysis:

Compound Ki was analyzed using Morrison ki fit model in XL-fit

-   -   a.        fit=(1−((((E+x)+(Ki*(1+(S/Kd))))−(((((E+x)+(Ki*(1+(S/Kd))))−2)−((4*E)*x))−0.5))/(2*E)))        -   res=(y-fit)    -   b. Parameters:    -   E=enzyme concentration    -   S=Tracer222 concentration, Kd=Tracer222 Kd        -   All measurements reported using the same units (uM)

Exemplary compounds of Formula I or Ia were tested in the bindingassays. The Ki values determined are listed in Tables B 1-1 and B 1-2.

TABLE B-1 Compound HPK1 K_(i) No. (μm), (Lanth)   1 0.0575   2 0.000391  3 0.0158   4 0.000333   5 0.000209   6 0.00654   7 0.0925   8 0.0196 13 0.0815  14 0.012  15 0.0195  16 0.00166  17 0.000366  18 0.0273  190.00541  20 0.027  21 0.61  22 0.024  23 0.083  24 1.16  25 1.61  260.199  27 0.0864  28 0.00194  30 0.0757  31 0.00527  32 0.0012  370.000351  38 0.249  39 0.000167  40 0.0219  41 0.00037  42 0.000627  430.129  44 0.0153  45 0.0138  46 0.00719  47 0.00251  48 0.919  49 0.0146 50 0.00671  51 0.0158  52 0.000533  54 0.000624  55 0.0435  56 0.0134 57 0.0338  59 0.0084  60 0.0115  61 0.0837  62 0.00167  63 0.0457  650.00345  66 0.00104  67 0.000823  68 0.0016  69 0.0167  70 0.00567  710.00354  72 0.000447  73 0.00496  74 0.000622  75 0.0232  76 0.0472  770.0129  78 0.0463  79 0.0241  80 0.00139  81 0.00316  82 0.00553  850.00103  86 0.00882  87 0.0653  88 0.015  89 0.00253  90 0.0439  910.019  92 0.000205  93 0.00253  94 0.0118  95 0.000738  98 0.00432  990.0453 100 0.0148 101 0.000204 102 0.000333 103 0.0137 104 0.00037 1050.0028 106 0.00581 107 0.00567 108 0.000191 109 0.046 110 0.024 1130.000273 (Ent-1), 0.0047 (Ent-2) 115 0.015 116 0.044 117 0.065 1180.0028 119 0.00252 (Ent-1), 0.00103 (Ent-2) 122 0.0032 123 0.0057 1240.014 125 0.016 126 0.086 127 0.000052 128 0.00025 130 0.0028 131 0.091132 0.024 133 0.0012 134 0.075 135 0.0032 136 0.045 138 2.3 139 0.0055140 0.22 143 0.007 144 0.013 145 0.0058 146 0.0025 147 0.0048 148 0.0038149 0.00119 150 0.0038 151 0.034 153 0.1 154 0.00026 155 0.013 1560.00037 157 0.019 159 0.014 160 0.41 161 0.0017 162 0.00035 163 0.0032164 0.0105 165 0.0148 166 0.0000816 167 0.00068 168 0.000082 169 0.00183170 0.023 171 0.0472 172 0.0102 173 0.0148 174 0.000204 175 0.00104 1760.00271 177 0.00896 178 0.0685 179 0.0101 180 0.0161 181 0.0571 1820.000584 183 0.000137 184 0.0256 185 0.000541 186 0.00696 187 0.0497 1880.000312 189 0.00544 190 0.00105 191 0.000187 192 0.0022 193 0.000148194 0.00079 195 0.000273 196 0.00021 197 0.00223 198 0.0046 199 0.00117200 0.00212 201 0.000299 202 0.000253 203 0.000363 204 0.000668 2050.00102 206 0.000485 207 0.0815 208 0.747 209 0.0000405 210 0.104 2110.0235 212 0.00376 213 0.000939 214 0.0000564 215 0.000101 216 0.0118217 0.00145 218 0.000844 219 0.0185 220 0.00326 221 0.0238 222 0.00326223 0.00202 224 0.00129 225 0.000583 226 0.00227 227 0.000079 2280.000015 229 0.000013 230 0.00015

TABLE B1-2 Compound HPK1 K_(i) (nM) No. L = Lanth; H = HTRF   9 0.016nM, H  10 0.228 nM, H  11 0.016 nM, H  12 0.054 nM, H  29 0.014 nM, H 33 0.013 nM, H  34 0.025 nM, H  35 0.013 nM, H  36 0.014 nM, H  530.020 nM, H  58 5.5 nM, H  64 0.13 nM, H  83 0.26 nM, H  84 1.4 nM, H 96 4.1 nm, H  97 15 nm, L 111 0.013 nM, H 112 0.168 nM, H 114 0.79 nM,H 120 27 nM, H 121 8.7 nM, H 129 1.33 nM, H 141 5.6 nM, H 142 789 nM, H152 2.1 nM, L 158 0.78 nM, H 191 0.19 nM, L 192 2.2 nM, L 227 0.078 nM,L 228 0.015 nM, H 229 0.013 nM, H 230 0.15 nM, H 231 0.128 nM, H 232 70nM, H 233 0.018 nM, H 234 0.021 nM, H 235 0.024 nM, H 236 1.49 nM, H 2371.66 nM, H 238 0.10 nM, H 239 0.11 nM, H 240 9 nM, H 241 30.6 nM, H 2420.22 nM, H 243 0.016 nM, H 244 1234 nM, H 245 16.6 nM, H 246 0.035 nM, H247 0.13 nM, H 248 86 nM, H 249 382 nM, H 250 16 nM, H 251 1.6 nM, H 2520.20 nM, H 253 284 nM, H 254 224 nM, H 255 0.796 nM, H 256 0.51 nM, H257 628 nM, H 258 150 nM, H 259 265 nM, H 260 514 nM, H 261 211 nM, H262 0.31 nM, H 263 1.43 nM, H 264 390 nM, H 265 2.2 nM, H 266 2.6 nM, H267 9.9 nM, H 268 5.8 nM, H 269 8.8 nM, H 270 22 nM, H 271 0.17 nM, H272 1.9 nM, H 273 0.14 nM, H 274 5.1 nM, H 275 0.15 nM, H 276 0.21 nM, H277 0.013 nM, H 278 0.96 nM, H 279 0.026 nM, H 280 1.8 nM, H 281 8.5 nM,H 282 0.91 nM, H 283 0.013 nM, H 284 1.1 nM, H 285 2.0 nM, H 286 0.013nM, H 287 0.27 nM, H 288 0.013 nM, H 289 0.24 nM, H 290 0.13 nM, H 2910.013 nM, H 292 15 nM, H 293 0.20 nM, H 294 23 nM, H 295 722 nM, H 296135 nM, H 297 255 nM, H 298 0.017 nM, H 299 0.017 nM, H 300 0.87 nM, H301 2.8 nM, H 302 0.365 nM, H 303 0.024 nM, H 304 2.1 nM, H 305 0.019nM, H 306 0.013 nM, H 307 0.084 nM, H 308 0.013 nM, H 309 0.017 nM, H310 0.013 nM, H 311 0.154 nM, H 312 0.015 nM, H 313 0.15 nM, H 314 0.39nM, H 315 0.013 nM, H 316 0.013 nM, H 317 0.043 nM, H 318 0.013 nM, H319 10.4 nM, H 320 42 nM, H 321 0.99 nM, H 322 0.86 nM, H 323 163.5 nM,H 324 975 nM, H 325 70 nM, H 326 n/a 327 122 nM, H 328 7.5 nM, H 32937.9 nM, H 330 50.12 nM, H 331 1.3 nM, H 332 4.6 nM, H 333 0.83 nM, H334 9.4 nM, H 335 0.22 nM, H 336 18 nM, L 337 2.8 nM, L 338 0.58 nM, H339 0.02 nM, H 340 0.02 nM, H 341 5 nM, L 342 2.1 nM, H 343 110 nM, H344 82 nM, H 345 383.7 nM, H 346 2.9 nM, L 347 7.2 nM, L 348 0.22 nM, L349 0.32 nM, L 350 2.4 nM, L 351 1.6 nM, L 352 0.72 nM, L 353 16 nM, L354 0.84 nM, L 355 1.3 nM, H 356 2.2 nM, L 357 0.026 nM, L 358 0.026 nM,L 359 0.21 nM, L 360 1.2 nM, L 361 0.033 nM, L 362 0.034 nM, L 363 0.13nM, L 364 5.9 nM, L 365 0.73 nM, L 366 3.6 nM, L 367 0.12 nM, L 3680.082 nM, L 369 25.6 nM, H 370 n/a 371 0.87 nM, L 372 95 nM, L 373 5.5nM, L 374 0.95 nM, L 375 0.33 nM, H 376 0.39 nM, H 377 12 nM, H 378 22nM, H 379 0.21 nM, L 380 5.8 nM, L 381 0.15 nM, L 382 2.7 nM, L 383 0.55nM, L 384 0.17 nM, L 385 8.3 nM, L 386 3.7 nM, L 387 0.168 nM, H 3880.50 nM, H 389 0.038 nM, H 390 1.4 nM, H

Example B2 Human T-Cell IL2 Induction Assay Assay Principle:

Anti-CD3 and anti-CD28 activates TCR signaling in primary human pan Tcells leading to IL-2 promoter induction. Secreted IL-2 in cell culturesupernatant is detected by electrochemiluminescence using a captureantibody against IL-2 and an anti-IL-2 antibody labeled with SULFO-tag.

Literature:

See www.mesoscale.com for additional electrochemiluminescence technologyinformation.

Assay Procedure:

Incubate primary human pan T cells with varying concentrations of testcompounds for 30 minutes in a humidified incubator at 37° C. and 5% CO₂.Transfer cells to a plate pre-coated with a fixed concentration ofanti-human CD3 (determined separately for each donor lot) and addsoluble anti-human CD28 (final concentration=1 μg/ml). Stimulate cellsin a humidified incubator at 37° C. and 5% CO₂ for 4 hours. Transfer 25μl of supernatant to a MSD single spot plate pre-coated with ananti-human IL-2 antibody. Incubate MSD plate overnight at 4° C. withgentle shaking. Wash MSD plate 4× with wash buffer. Add SULFO-taggeddetection antibody at a 1:50 dilution and incubate at room temperatureshaking for 2 hours. Wash MSD plate 4× with wash buffer and add 150 μl2× MSD read buffer. Read on an MSD instrument. Normalize data tostimulated/untreated controls to calculate % activity at eachconcentration of compound.

Materials:

Frozen Primary Human Pan-T Cells (StemCell Technologies #70024)

anti-human CD3 (OKT3 clone) (eBioscience #16-0037-81)

anti-human CD28 (CD28.2 clone) (BD #555725)

96-well Human IL-2 tissue culture kit (MSD #K151AHB-4)

Instrumentation:

Biomek FX for liquid handling (Beckman Coulter)

MSD SECTOR S 600 (Meso Scale Discovery)

Exemplary compounds of Formula I or Ia were tested in the human T-cellIL-2 induction assays. The % increase measured for IL-2 in cells treatedby the test compounds relative to untreated cells are provided in TableB2 for certain compounds.

TABLE B2 Com- % IL-2 increase Assayed pound relative to concentrationNo. untreated cells (μM) 135 800% 8.3 158 343% 0.93 161 243% 2.8 162 73% 0.93 168 323% 0.31 233 521% 0.034 266 438% 0.93 276 1157%  0.31 279333% 0.10 284 529% 0.93 302 732% 2.8 315 480% 0.31 327 331% 25

It is to be noted that the term “a” or “an” entity refers to one or moreof that entity; for example, “a polypeptide” is understood to representone or more polypeptides. As such, the terms “a” (or “an”), “one ormore,” and “at least one” can be used interchangeably herein.

All technical and scientific terms used herein have the same meaning.Efforts have been made to ensure accuracy with respect to numbers used(e.g. amounts, temperature, etc.) but some experimental errors anddeviations should be accounted for.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise. It is understood that embodimentsdescribed herein include “consisting of” and/or “consisting essentiallyof” embodiments.

As used herein, the term “about,” when referring to a value is meant toencompass variations of, in some embodiments ±50%, in some embodiments±20%, in some embodiments ±10%, in some embodiments ±5%, in someembodiments ±1%, in some embodiments ±0.5%, and in some embodiments±0.1% from the specified amount, as such variations are appropriate toperform the disclosed methods or employ the disclosed compositions.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit, unlessthe context clearly dictates otherwise, between the upper and lowerlimit of the range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these small ranges which may independently be included in thesmaller rangers is also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the invention.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

FURTHER EMBODIMENTS

Embodiment 1. A compound of Formula I:

wherein,

R₁ is hydrogen, halogen, methyl, CF₃, CHF₂, CH₂OH, or cyano;

R₂ is:

-   -   a 5-10 member heteroaryl or 5-10 member heterocyclyl, having 1-4        heteroatoms selected from O, S, and N; and optionally        substituted with one, two, three or four substituents, R₆, R₇,        R₅ and R_(8′), each of which is independently selected from the        group consisting of:        -   i. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆            alkenylene, wherein said alkyl, alkenyl and alkenylene can            be optionally substituted with one to four hydroxyl,            halogen, nitrile, amino, mono(C₁₋₆)alkylamino-,            di(C₁₋₆)alkylamino-, —SO₂R^(y), SONR^(y), —(CO)NR^(y)R^(z)            or —NR^(y)(CO)R^(z), wherein R^(y) and R^(z), in each            instance, is independently hydrogen or C₁₋₆ alkyl, wherein            said alkyl can optionally be substituted with one to four            hydroxyl or halogen;        -   ii. NR^(y)R^(z)—C(O)—, wherein R^(y) and R^(z) are each            independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can            optionally be substituted with one to four hydroxyl or            halogen;        -   iii. hydroxy(C₁₋₆)alkyl;        -   iv. C₁₋₆ alkoxy, wherein said alkoxy can be optionally            substituted with one to four hydroxyl or halogen;        -   v. C₃₋₉ cycloalkyl, substituted or unsubstituted C₆ aryl,            substituted or unsubstituted 5-member heteroaryl, or C₂₋₉            heterocyclyl;        -   vi. halogen;        -   vii. amino;        -   viii. cyano;        -   ix. —NR^(y)(CO)R^(z), wherein R^(y) and R^(z) are each            independently hydrogen or C₁₋₆ alkyl, wherein said alkyl can            optionally be substituted with one to four hydroxyl or            halogen;        -   x. —SO₂R′, wherein R′ is H or C₁₋₆ alkyl;        -   xi. —SO₂NR′R″, wherein R′ and R″ are independently H or C₁₋₆            alkyl; and        -   xii. wherein a carbon embedded in said heterocyclyl taken            together with    -   an oxygen to which it is bound can form a carbonyl; or

R₂ is C₆₋₁₀ aryl having one, two, three or four substituents selectedfrom the group consisting of branched or linear C₁₋₆ alkyl, C₁₋₆alkenyl, C₁₋₆ alkenylene, C₃₋₄ cycloalkyl, wherein said alkyl, alkenyl,alkenylene and cycloalkyl can be substituted with amino, hydroxyl,cyano, halogen, amide, mono(C₁₋₆)alkylamino-, di(C₁₋₆)alkylamino-,—SO₂R^(c), SONR^(d), —(CO)NR^(c)R^(d) and —NR^(c)(CO)R^(d),

-   -   wherein R^(c) and R^(d) are each independently selected from the        group consisting of hydrogen and C₁₋₆ alkyl, wherein said alkyl        can be optionally substituted with one to four hydroxyl or        halogen; or

R₂ is hydrogen or —SO₂NH₂;

R₃ is C₁₋₆ alkyl, hydrogen, cyano, or halogen; and

R₄ is A-C(O)—, wherein, A is:

-   -   i. C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, or C₂₋₉ heterocyclyl,        wherein said cycloalkyl, heteroaryl, or heterocyclyl can be        optionally substituted with one, two, three or four of R₅,        wherein R₅ is selected from the group consisting of hydrogen,        branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkenyl,        C₁₋₆ alkenylene, wherein said alkyl, alkenyl and alkenylene can        be substituted with amino, C₁₋₆ alkoxy, hydroxyl, halogen,        —SO₂R^(e) and amide; halogen, hydroxy(C₁₋₆)alkyl,        halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, hydroxyl, C₁₋₆ alkoxy,        amino, C₂₋₉ heteroaryl, —SO₂R^(c), and NR^(c)R^(f)—C(O)—,        wherein R^(e) and R^(f) are independently selected from the        group consisting of hydrogen and branched or linear C₁₋₆ alkyl;

or, said cycloalkyl or heterocyclyl together with two of R₅ form abicyclic or spiro ring, wherein two of R₅ attached to different atomsare taken together with the carbon to which each is attached to form abicyclic, or two of R₅ attached to the same carbon are taken togetherwith the carbon to which each is attached to form a spiro ring; and

-   -   ii. —NHR^(g), wherein R^(g) is selected from the group        consisting of:        -   a. branched or linear C₁₋₆ alkyl, C₃₋₅ cycloalkyl C₁₋₆            alkenyl, C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, and C₃₋₇            cycloalkyl, wherein said alkyl, alkenyl, alkenylene,            heterocyclyl and cycloalkyl can be optionally substituted            with hydroxyl, halogen, —CF₂, —CF₃, amino,            di(C₁₋₆)alkylamino, mono(C₁₋₆)alkylamino, cyano, C₃₋₇            cycloalkyl, C₁₋₆ alkoxy, —SO₂R′, —SO₂NR′R″, —(CO)NR′R″, or            —NR′(CO)R″, wherein R′ and R″ are independently H or C₁₋₆            alkyl; and        -   b. C₂₋₉ heteroaryl or C₆₋₁₀ aryl, wherein said heteroaryl            has 1-4 heteroatoms selected from O, S and N; and wherein            said aryl and heteroaryl can be optionally substituted with            one, two, three or four substituents selected from the group            consisting of branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl,            C₁₋₆ alkenylene, C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl,            hydroxyl, halogen, —CF₂, —CF₃, amino, di(C₁₋₆)alkylamino,            mono(C₁₋₆)alkylamino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,            —SO₂R′, —SO₂NR′R″, —(CO)NR′R″, and —NR′(CO)R″, wherein R′            and R″ are independently H or C₁₋₆ alkyl;

or, R₄ is D, wherein D is:

-   -   a 5-10 member heteroaryl, having 1-4 heteroatoms selected from        O, S, and N; and optionally substituted with one, two, three or        four substituents.

Embodiment 2. The compound of embodiment 1, wherein R₃ is hydrogen.

Embodiment 3. The compound of embodiment 2, wherein R₁ is hydrogen,fluoro or cyano.

Embodiment 4. The compound of embodiment 3, wherein R₅ is other thanhydrogen.

Embodiment 5. The compound of embodiment 4, wherein R₄ is A-C(O)—,wherein, A is:

wherein, v is zero, one, two, three or four; X, Y and Z are eachindependently absent or —CH₂—, and wherein, if present, zero, one or twoof H on each of X, Y and Z can be R₅.

Embodiment 6. The compound of embodiment 4, wherein R₄ is A-C(O)—,wherein,

A is:

wherein, v is zero, one, two, three or four; X, Y and Z are eachindependently absent or —CH₂—, and wherein, if present, zero, one or twoof H on each of X, Y and Z can be R₅.

Embodiment 7. The compound of embodiment 2, wherein R₄ is A-C(O)—,wherein, A is:

wherein, v is zero, one or two.

Embodiment 8. The compound of embodiment 7, wherein A is:

wherein, v is zero, one or two.

Embodiment 9. The compound of embodiment 8, wherein R₅ is other thanhydrogen and A is:

Embodiment 10. The compound of embodiment 7, wherein A is:

wherein, v is zero, one or two.

Embodiment 11. The compound of embodiment 10, wherein R₅ is other thanhydrogen and A is:

Embodiment 12. The compound of embodiment 2, wherein R₅ is selected fromthe group consisting of hydrogen, fluorine, cyano, NH₂—C(O)—, C₂₋₉heteroaryl, cyano(C₁₋₆)alkyl, and hydroxy(C₁₋₆)alkyl.

Embodiment 13. The compound of embodiment 12, wherein R₅ is fluoro orcyano.

Embodiment 14. The compound of embodiment 13, having one of thefollowing structures:

Embodiment 15. The compound of embodiment 12, wherein R₅ is C₂₋₉heteroaryl.

Embodiment 16. The compound of embodiment 15, wherein said C₂₋₉heteroaryl is an optionally substituted heteroaryl containing at leastone nitrogen.

Embodiment 17. The compound of embodiment 16, wherein said heteroaryl isan optionally substituted 5-member heteroaryl containing 1 or 2 nitrogenatoms.

Embodiment 18. The compound of embodiment 17, wherein said 5-memberheteroaryl is an optionally substituted pyrazole.

Embodiment 19. The compound of embodiment 18, having one of thefollowing structures:

Embodiment 20. The compound of embodiment 12, wherein at least one R₅ iscyano(C₁₋₆)alkyl.

Embodiment 21. The compound of embodiment 20, wherein at least one R₅ iscyano-CH₂—.

Embodiment 22. The compound of embodiment 21, having one of thefollowing structures:

Embodiment 23. The compound of embodiment 12, wherein R₅ is hydrogen.

Embodiment 24. The compound of embodiment 23, having one of thefollowing structures:

Embodiment 25. The compound of embodiment 1, wherein R₄ is D, andwherein D is an optionally substituted heteroaryl containing at leastone nitrogen.

Embodiment 26. The compound of embodiment 25, wherein said heteroaryl isan optionally substituted 5-member heteroaryl containing 1 or 2 nitrogenatoms.

Embodiment 27. The compound of embodiment 26, wherein said 5-memberheteroaryl is an optionally substituted pyrazole.

Embodiment 28. The compound of embodiment 27, wherein said optionallysubstituted pyrazole is

wherein the wavy line denotes the point of attachment to the N; andwherein R^(A) is branched or linear C₁₋₆ alkyl, wherein said alkyl canbe optionally substituted with one to four hydroxyl, halogen, nitrile,amino, mono(C₁₋₆)alkylamino-, di(C₁₋₆)alkylamino-, or —NR^(y)(CO)R^(z),wherein R^(y) and R^(z), in each instance, is independently hydrogen orC₁₋₆ alkyl.

Embodiment 29. The compound of embodiment 28, wherein R^(A) is linearC₁₋₆ alkyl substituted with hydroxyl, halogen, nitrile, or amino.

Embodiment 30. The compound of embodiment 29, wherein said linear C₁₋₆alkyl is ethyl substituted with nitrile.

Embodiment 31. The compound of embodiment 30, wherein R^(A) is

Embodiment 32. The compound of embodiment 31, wherein R^(A) is

Embodiment 33. The compound of embodiment 31, having one of thefollowing structures:

Embodiment 34. The compound of embodiment 1, wherein R₂ is an optionallysubstituted 5-10 member heteroaryl or an optionally substituted 5-10member heterocyclyl.

Embodiment 35. The compound of embodiment 34, wherein R₂ is selectedfrom the group consisting of:

each of which can be optionally substituted at with one, two or threesubstituents, R₆, R₇ and R₈.

Embodiment 36. The compound of embodiment 35, wherein R₂ is:

Embodiment 37. The compound of embodiment 36, wherein R₂ is:

Embodiment 38. The compound of embodiment 37, wherein R₂ is:

Embodiment 39. The compound of embodiment 38, wherein R₂ is:

Embodiment 40. The compound of embodiment 39, wherein R₆ is C₁₋₆ alkylor hydroxy(C₁₋₆)alkyl.

Embodiment 41. The compound of embodiment 40, wherein R₆ is methyl.

Embodiment 42. The compound of embodiment 41, having one of thefollowing structures:

Embodiment 43. The compound of embodiment 35, wherein R₂ is:

Embodiment 44. The compound of embodiment 43, wherein R₂ is:

Embodiment 45. The compound of embodiment 44, wherein R₂ is:

Embodiment 46. The compound of embodiment 45, wherein R₆ is branched orlinear C₁₋₆ alkyl, wherein said alkyl can be optionally substituted withone to four hydroxyl or halogen.

Embodiment 47. The compound of embodiment 46, wherein R₂ is:

Embodiment 48. The compound of embodiment 47, having one of thefollowing structures:

Embodiment 49. The compound of embodiment 35, wherein R₂ is:

Embodiment 50. The compound of embodiment 49, wherein R₂ is:

Embodiment 51. The compound of embodiment 50, wherein R₆ is branched orlinear C₁₋₆ alkyl.

Embodiment 52. The compound of embodiment 51, wherein R₆ is methyl,ethyl or isopropyl.

Embodiment 53. The compound of embodiment 52, having one of thefollowing structures:

Embodiment 54. The compound of embodiment 35, wherein R₂ is:

Embodiment 55. The compound of embodiment 54, wherein R₂ is:

Embodiment 56. The compound of embodiment 55, wherein R₂ is:

Embodiment 57. The compound of embodiment 56, wherein R₆is branched orlinear C₁₋₆ alkyl.

Embodiment 58. The compound of embodiment 57, wherein R₆is methyl.

Embodiment 59. The compound of embodiment 58, having one of thefollowing structures:

Embodiment 60. The compound of embodiment 35, wherein R₂ is:

Embodiment 61. The compound of embodiment 35, wherein one of R₆, R₇ andR₅ is O and together with the carbon to which it is attached forms acarbonyl.

Embodiment 62. The compound of embodiment 61, wherein R₂ is

wherein R₇ is hydrogen or C₁₋₆ alkyl.

Embodiment 63. The compound of embodiment 62, having one of thefollowing structures:

Embodiment 64. The compound of embodiment 1, having one of the followingstructures:

Embodiment 65. A pharmaceutical composition comprising a compound of anyone of embodiments 1-64 and a pharmaceutically acceptable carrier.

Embodiment 66. The pharmaceutical composition of embodiment 65, whereinsaid composition further comprises a chemotherapeutic agent.

Embodiment 67. The pharmaceutical composition of embodiment 66, whereinsaid chemotherapeutic agent is an immunotherapeutic agent.

Embodiment 68. A method of inhibiting HPK1, said method comprisingcontacting HPK1 with an effective amount of a compound of any one ofembodiments 1-64 or a pharmaceutical composition of any one ofembodiments 65-67.

Embodiment 69. A method for enhancing an immune response in a subject inneed thereof, wherein the method comprises administering to said subjectan effective amount of a compound of any one of embodiments 1-64 or apharmaceutical composition of any one of embodiments 65-67.

Embodiment 70. The method of embodiment 69, wherein T cells in thesubject have at least one of enhanced priming, enhanced activation,enhanced migration, enhanced proliferation, enhanced survival, andenhanced cytolytic activity relative to prior to the administration ofthe compound or pharmaceutical composition.

Embodiment 71. The method of embodiment 70, wherein the T cellactivation is characterized by an elevated frequency of γ-IFN⁺ CD8 Tcells or enhanced levels of IL-2 or granzyme B production by T cellsrelative to prior to administration of the compound or pharmaceuticalcomposition.

Embodiment 72. The method of embodiment 71, wherein the number of Tcells is elevated relative to prior to administration of the compound orpharmaceutical composition.

Embodiment 73. The method of any one of embodiments 70-72, wherein the Tcell is an antigen-specific CD8 T cell.

Embodiment 74. The method of embodiment 73, wherein the antigenpresenting cells in the subject have enhanced maturation and activationrelative prior to the administration of the compound or pharmaceuticalcomposition.

Embodiment 75. The method of embodiment 74, wherein the antigenpresenting cells are dendritic cells.

Embodiment 76. The method of embodiment 74, wherein the maturation ofthe antigen presenting cells is characterized by increased frequency ofCD83⁺ dendritic cells.

Embodiment 77. The method of embodiment 74, wherein the activation ofthe antigen presenting cells is characterized by elevated expression ofCD80 and CD86 on dendritic cells.

Embodiment 78. The method of any one of embodiments 68-77, wherein saidsubject has cancer.

Embodiment 79. A method for treating a HPK1-dependent disorder, saidmethod comprising administering to a subject in need thereof aneffective amount of a compound of any one of embodiments 1-64 or apharmaceutical composition of any one of embodiments 65-67.

Embodiment 80. The method of embodiment 79, wherein said HPK1-dependentdisorder is a cancer.

Embodiment 81. The method of embodiment 78 or 80, wherein the cancercomprises at least one cancer selected from the group consisting ofcolorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer,breast cancer, pancreatic cancer, a hematological malignancy, and arenal cell carcinoma.

Embodiment 82. The method of any one of embodiments 78, 80, or 81,wherein the cancer has elevated levels of T-cell infiltration.

Embodiment 83. The method of any one of embodiments 78, 80, 81, or 82,wherein the cancer cells in the subject selectively have elevatedexpression of MHC class I antigen expression relative to prior to theadministration of the compound or composition.

Embodiment 84. The method of any one of embodiments 78, 80, 81, 82, or83, wherein said method further comprises administering achemotherapeutic agent to said subject.

Embodiment 85. The method of embodiment 84, wherein saidchemotherapeutic agent is administered to said subject simultaneouslywith said compound or said composition.

Embodiment 86. The method of embodiment 84, wherein saidchemotherapeutic agent is administered to said subject prior toadministration of said compound or said composition.

Embodiment 87. The method of embodiment 84, wherein saidchemotherapeutic agent is administered to said subject afteradministration of said compound or said composition.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein, R₁ is hydrogen,halogen, cyano, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆ alkoxyl, optionally substituted amino oroptionally substituted acylamino; R₂ is (a), (b), (c), (d), (e), (f),(g) or (h): (a) a 5-10 membered heteroaryl or 5-10 memberedheterocyclyl, having 1-4 heteroatoms selected from O, S, and N; andoptionally substituted with one, two, three, four or five substituents;or (b) a C₆₋₁₀ aryl optionally substituted with one, two, three, four orfive substituents; or (c) hydrogen, halogen, cyano, —NR^(b)C(O)R^(a),—NR^(b)SO₂R^(a), —SO₂NR^(a)R^(b); or —SO₂R^(a); wherein each R^(a) isindependently C₁₋₆ alkyl, and R^(b) is independently hydrogen or C₁₋₆alkyl; or R^(a) and R^(b) are taken together with the atom(s) to whichthey are attached to form an optionally substituted 5-10 memberedheterocyclyl; or (d) —OR^(a1) or —(C₁₋₆ alkylene)-OR^(a1); wherein eachR^(a1) is independently C₁₋₆ alkyl optionally substituted with C₆₋₁₀aryl; 5-10 membered heteroaryl; or 5-10 membered heterocyclyl; whereinthe C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclylare optionally substituted; or (e) a C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl, each optionally substituted with one to five substituents; or(f) a C₃₋₈ cycloalkyl optionally substituted with one to fivesubstituents; (g) —C(O)NR^(a2)R^(b2) or NR^(a2)(CO)R^(b2), wherein eachR^(a2) is independently hydrogen or C₁₋₆ alkyl, and R^(b2) is hydrogen,C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl or 5-10 memberedheterocyclyl; or R^(a2) and R^(b2) are taken together with the atom(s)to which they are attached to form an optionally substituted 5-10membered heterocyclyl; wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl and 5-10 membered heterocyclyl are optionally substituted; or(h) 5-10 membered heteroaryl fused with a ring selected from the groupconsisting of 5 or 6 membered heteroaryl, 5-10 membered heterocyclyl,C₆₋₁₀ aryl and C₃₋₇ cycloalkyl, wherein the 5-10 membered heteroaryl ofR₂ and the fused ring are optionally substituted with one to foursubstituents; R₃ is hydrogen, cyano, halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₉ heterocyclyl, or optionallysubstituted C₁₋₆ alkoxy; and R₄ is A-C(O)— or D; A is C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₉ heteroaryl, C₂₋₉ heterocyclyl, —NHR^(g) or —OR^(h);wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 7 C₂₋₉ heteroaryl and C₂₋₉heterocyclyl of A are optionally substituted independently with one,two, three, four or five substituents; R^(g) and R^(h) are independentlyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, C₂₋₉ heteroaryl,or C₂₋₉ heterocyclyl; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, C₆₋₁₀ aryl, C₂₋₉ heteroaryl and C₂₋₉ heterocyclyl of R^(g)and R^(h) are optionally substituted independently with one, two, three,four or five substituents; and D is hydrogen, a C₆₋₁₀ aryl, or a 5-10membered heteroaryl having 1-4 heteroatoms selected from O, S, and N; ora 5-10 membered heteroaryl fused with a ring selected from the groupconsisting of 5- or 6-membered heteroaryl, 5-10 membered heterocyclyl,C₆ aryl and C₃₋₈ cycloalkyl; wherein the 5-10 membered heteroaryl of Dand the fused ring are optionally substituted with one, two, three, fouror five substituents; provided that the compound is other than compoundsselected from the group consisting ofN-(8-amino-3-isoquinolinyl)-N′-ethyl-urea,5-[(8-amino-3-isoquinolinyl)amino]-2-pyrazinecarbonitrile, and5-[(8-amino-3-isoquinolinyl)amino]-3-[(1R)-2-(dimethylamino)-1-methylethoxy]-2-pyrazinecarbonitrile,and pharmaceutically acceptable salts thereof.
 2. The compound of claim1, wherein R₂ is a 5-10 membered heteroaryl or 5-10 memberedheterocyclyl, having 1-4 heteroatoms selected from O, S, and N; andoptionally substituted with one, two, three, four or five substituents.3. The compound of claim 2, wherein R₂ is selected from the groupconsisting of:

each of which can be optionally substituted.
 4. The compound of claim 2,wherein R₂ is selected from the group consisting of:

each of which is optionally substituted.
 5. The compound of claim 4,wherein R₂ is:

wherein R₆, R₇, and R₅ are each independently selected from the groupconsisting of: i. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆alkenylene, wherein said alkyl, alkenyl and alkenylene can be optionallysubstituted with one to four substituents independently selected fromthe group consisting of hydroxyl, halogen, nitrile, amino,mono(C₁₋₆a1kyl)amino-, di(C₁₋₆alkyl)amino-, —SO₂R^(y), —S(O)NR^(y),—(CO)NR^(y)R^(z) and —NR^(y)(CO)R^(z), wherein R^(y) and R^(z), in eachinstance, is independently hydrogen or C₁₋₆ alkyl, wherein said alkylcan optionally be substituted with one to four substituentsindependently selected from the group consisting of hydroxyl andhalogen; ii. NR^(y)R^(z)—C(O)—, wherein R^(y) and R^(z) are eachindependently hydrogen or C₁₋₆ alkyl, wherein said alkyl can optionallybe substituted with one to four substituents independently selected fromthe group consisting of hydroxyl and halogen; iii. hydroxy(C₁₋₆ alkyl);iv. C₁₋₆ alkoxy, wherein said alkoxy can be optionally substituted withone to four substituents independently selected from the groupconsisting of hydroxyl and halogen; v. C₃₋₉ cycloalkyl, substituted orunsubstituted C₆ aryl, substituted or unsubstituted 5-memberedheteroaryl, or C₂₋₉ heterocyclyl; vi. halogen; vii. amino; viii. cyano;ix. —NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are each independentlyhydrogen or C₁₋₆ alkyl, wherein said alkyl can optionally be substitutedwith one to four substituents independently selected from the groupconsisting of hydroxyl and halogen; x. —SO₂R′, wherein R′ is H or C₁₋₆alkyl; xi. —SO₂NR′R″, wherein R′ and R″ are independently H or C₁₋₆alkyl; xii. —NR′C(O)OR″, —NR′SO₂NR″ or —NR′S(O)R″, wherein R′ isindependently H or C₁₋₆ alkyl and R″ is independently C₁₋₆ alkyl,halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl optionally substituted with C₁₋₆ alkyl;and xiii. wherein a carbon embedded in said heterocyclyl taken togetherwith an oxygen to which it is bound can form a carbonyl.
 6. The compoundof claim 5, wherein R₂ is:


7. The compound of claim 6, wherein R₂ is:


8. The compound of claim 7, wherein R₂ is:

wherein R₆, R₇, and R⁸ are each independently selected from the groupconsisting of hydrogen, hydroxyl, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, andmono(C₁₋₆ alkyl)amino.
 9. The compound of claim 8, wherein R₆ is C₁₋₆alkyl; R₇ is hydrogen, amino, or mono(C₁₋₆ alkyl)amino; and R₅ ishydrogen, hydroxyl, or C₁₋₆ alkoxy.
 10. The compound of claim 9, whereinR₆ is methyl.
 11. The compound of claim 10, wherein R₇ is amino.
 12. Thecompound of claim 10, wherein R₂ is


13. The compound of claim 1, wherein R₄ is -A-C(O)—.
 14. The compound ofclaim 13, wherein A is: i. C₃₋₇ cycloalkyl, C₂₋₉ heteroaryl, or C₂₋₉heterocyclyl, wherein said cycloalkyl, heteroaryl, or heterocyclyl canbe optionally substituted with one, two, three or four of R₅, wherein R₅is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenylene, halogen, cyano, hydroxyl,C₁₋₆ alkoxy, optionally substituted C₂₋₉ heteroaryl, —SO₂R^(e),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)SO₂R^(f) and NR^(e)R^(f)—C(O)—;wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyleneof R₅ can be optionally substituted with one to four substituentsindependently selected from the group consisting of C₁₋₆ alkoxy,hydroxyl, halogen, cyano, —SO₂R^(e), —NR^(e)R^(f)—NR^(e)C(O)R^(f) and—C(O)NR^(e)R^(f), wherein R^(e) and R^(f) in each occurrence areindependently selected from the group consisting of hydrogen, branchedor linear C₁₋₆ alkyl and C₃₋₇ cycloalkyl; or, said cycloalkyl orheterocyclyl together with two of R₅ form a bicyclic or spiro ring,wherein two of R₅ attached to different atoms are taken together withthe carbon to which each is attached to form a bicyclic, or two of R₅attached to the same carbon are taken together with the carbon to whicheach is attached to form a spiro ring; ii. —NHR^(g) or —OR^(h), whereinR^(g) and R^(h) are independently selected from the group consisting of:a. branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkenylene, C₂₋₉heterocyclyl, and C₃₋₇ cycloalkyl, wherein said alkyl, alkenyl,alkenylene, heterocyclyl and cycloalkyl can be optionally substitutedwith one to four substituents independently selected from the groupconsisting of hydroxyl, halogen, —CHF₂, —CF₃, amino, di(C₁₋₆alkyl)amino, mono(C₁₋₆ alkyl)amino, cyano, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,—SO₂R′, —SO₂NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′C(O)NR″R″′,—NR′SO₂NR″R′″ or —NR′S(O)R″, wherein R′ and R′″ are independently H orC₁₋₆ alkyl and R″ is independently C₁₋₆ alkyl, halo(C₁₋₆ alkyl) or C₆₋₁₀aryl optionally substituted with C₁₋₆ alkyl; or R″ and R′″ are takentogether with the nitrogen to which they are attached to form asubstituted or unsubstituted heterocyclyl; and b. C₂₋₉ heteroaryl orC₆₋₁₀ aryl, wherein said heteroaryl has 1-4 heteroatoms selected from O,S and N; and wherein said aryl and heteroaryl can be optionallysubstituted with one, two, three or four substituents selected from thegroup consisting of branched or linear C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆alkenylene, C₂₋₉ heterocyclyl, C₃₋₇ cycloalkyl, hydroxyl, halogen,—CHF₂, —CF₃, amino, di(C₁₋₆ alkyl)amino, mono(C₁₋₆ alkyl)amino, cyano,C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, —SO₂R′, —SO₂NR′R″, —C(O)NR′R″, and—NR′C(O)R″, wherein R′ and R″ are independently H or C₁₋₆ alkyl; or iii.C₁₋₆ alkyl optionally substituted with one to four substituentsindependently selected from the group consisting of hydroxyl, halogen,cyano, C₁₋₆ alkoxy, amino, mono(C₁₋₆ alkyl)amino, di(C₁₋₆ alkyl)amino,C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 5-10 memberedheterocyclyl, —SO₂R′, —SO₂NR′R″, —C(O)NR′R″, —NR′C(O)R″, —NR′C(O)OR″,—NR′C(O)NR″R′″, —NR′SO₂NR″R′″ and —NR′S(O)R″; wherein R′ and R′″ areindependently H or C₁₋₆ alkyl and R″ is independently C₁₋₆ alkyl,halo(C₁₋₆ alkyl) or C₆₋₁₀ aryl optionally substituted with C₁₋₆ alkyl;or R″ and R′″ are taken together with the nitrogen to which they areattached to form an optionally substituted C₃₋₇ heterocyclyl.
 15. Thecompound of claim 14, wherein A is optionally substituted C₃₋₇cycloalkyl.
 16. The compound of claim 15, wherein R₄ is:

wherein, v is 0, 1, 2 or 3; and R₅ is selected from the group consistingof C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenylene, halogen,cyano, hydroxyl, C₁₋₆ alkoxy, optionally substituted C₂₋₉ heteroaryl,—SO₂R^(e), —NR^(e)R^(f), —NR^(e)C(O)R^(f), —NReSO₂R^(f) andNR^(e)R^(f)—C(O)—; wherein the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkenylene of R₅ can be optionally substituted with one tofour substituents independently selected from the group consisting ofC₁₋₆ alkoxy, hydroxyl, halogen, cyano, —SO₂R^(e),—NR^(e)R^(f)—NR^(e)C(O)R^(f) and —C(O)NR^(e)R^(f), wherein R^(e) andR^(f) in each occurrence are independently selected from the groupconsisting of hydrogen, branched or linear C₁₋₆ alkyl and C₃₋₇cycloalkyl.
 17. The compound of claim 16, wherein each R₅ isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, halogen, cyano, hydroxyl, C₁₋₆ alkoxy, and C₂₋₉heteroaryl, wherein said alkyl, cycloalkyl, and heteroaryl areoptionally substituted.
 18. The compound of claim 17, wherein at leastone R₅ is C₁₋₆ alkyl.
 19. The compound of claim 18, wherein said C₁₋₆alkyl is methyl or ethyl.
 20. The compound of claim 17, wherein one ofR₅ is optionally substituted C₂₋₉ heteroaryl.
 21. The compound of claim20, wherein said optionally substituted C₂₋₉ heteroaryl is an optionallysubstituted C₃ heteroaryl.
 22. The compound of claim 21, wherein saidoptionally substituted C₃ heteroaryl is an optionally substitutedpyrazole.
 23. The compound of claim 22, wherein said optionallysubstituted pyrazole is

wherein the wavy line denotes the point of attachment to the cyclopropylring; and wherein R^(B1) is C₁₋₆ alkyl.
 24. The compound of claim 17,wherein R₄ is:


25. The compound of claim 1, wherein R₄ is D.
 26. The compound of claim25, wherein D is a 5-10 membered heteroaryl, having 1-4 heteroatomsselected from O, S, and N; and optionally substituted with one, two,three or four substituents, wherein two of the substituents attached todifferent atoms are taken together with the atom to which each isattached to form a bicyclic or tricyclic, wherein said bicyclic ortricyclic is optionally substituted; or the 5-10 membered heteroaryl isfused with a ring selected from the group consisting of 5 or 6 memberedheteroaryl, 5-10 membered heterocyclyl, C₆ aryl and C₃₋₈ cycloalkyl,wherein the 5-10 membered heteroaryl of D and the fused ring areoptionally substituted, wherein said fused ring forms an optionallysubstituted bicyclic or tricyclic system.
 27. The compound of claim 26,wherein D is an optionally substituted heteroaryl containing at leastone nitrogen.
 28. The compound of claim 27, wherein said optionallysubstituted 5-member heteroaryl is an optionally substituted pyrazole.29. The compound of claim 28, wherein said optionally substitutedpyrazole is fused with another cyclic moiety to form an optionallysubstituted bicyclic or tricyclic.
 30. The compound of claim 29, whereinsaid bicyclic or tricyclic is

wherein X′ and Y′ are each independently C, N, S, or O; and wherein saidbicyclic is optionally substituted with one, two, three or foursubstituents independently selected from the group consisting ofhydrogen, hydroxyl, amino and C₁₋₆ alkyl; and wherein two of thesubstituents taken together with the atoms to which they are attachedcan form a C₃-C₅ spiro or a C₂₋₉ heteroaryl ring; wherein said C₂₋₉heteroaryl ring may be fused to said bicyclic to form a tricyclic. 31.The compound of claim 30, wherein at least one of X′ or Y′ are N. 32.The compound of claim 30, wherein said bicyclic or tricyclic is:


33. The compound of claim 25, wherein D is a 5-membered heteroarylhaving the formula

or a 6-membered heteroaryl having the formula wherein: Q is NR²⁰, CR²⁰,O or S; each T is independently N or CR²¹; each Z is independently N orC, provided that only one Z is N; each R²⁰ and R²¹ is independentlyhydrogen, alkyl, haloalkyl, alkoxy, halogen, hydroxy, or cyano; and R²²and R²³ are taken together with the atoms to which they are attached toform a bicyclic; wherein the bicyclic may contain one or moreheteroatoms selected from N, S and O; and wherein the bicyclic isoptionally substituted with one, two, three, four or five R³⁰; whereineach R³⁰ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocyclyl, halogen, cyano, oxo, —NR³¹R³², —SO₂NR³¹R³²,—C(O)NR³¹R³², —C(O)OR³³, —OR³³, —NR³³C(O)R³⁴, —NR³³SO₂R³⁵ or —SO₂R³⁵;wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl and C₃₋₇heterocyclyl of R³⁰ are optionally substituted with one to four R⁴⁰; ortwo R³⁰ groups are taken together with the parent moiety to with theyare attached to form a ring which is optionally substituted with one tofour R⁴⁰; each R³¹ and R³² is independently hydrogen or C₁₋₆ alkyl; orR³¹ and R³² are taken together with the nitrogen atom to which they areattached to form a C₃₋₇ heterocyclyl optionally substituted with one tofour R⁴⁰; each R³³ and R³⁴ are independently hydrogen or C₁₋₆ alkyl; R³⁵is C₁₋₆ alkyl; each R⁴⁰ is independently selected from the groupconsisting of halogen, cyano, oxo, —NR₄₁R₄₂, —SO₂NR⁴¹R⁴², —C(O)NR⁴¹R⁴²,—C(O)OR₄₃, —OR⁴³, —NR⁴³C(O)R⁴⁴, —NR⁴³SO₂R⁴⁵ or —SO₂R⁴⁵; C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₉ heteroaryl, C₆₋₁₀ aryl, oxo; or two R⁴⁰ groups are takentogether with the parent moiety to with they are attached to form a ringwhich is optionally substituted with one to three substituents selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl and oxo; each R⁴¹ and R⁴² isindependently hydrogen or C₁₋₆ alkyl; or R⁴¹ and R⁴² are taken togetherwith the nitrogen atom to which they are attached to form a C₃₋₇heterocyclyl optionally substituted with one to three substituentsselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl and oxo; each R⁴³ andR⁴⁴ are independently hydrogen or C₁₋₆ alkyl; and R⁴⁵ is C₁₋₆ alkyl. 34.The compound of claim 33, wherein D is

wherein q is 0, 1, 2, 3, 4, 5 or 6; R³⁶ is independently hydrogen orR³⁰; and R²⁰ and R³⁰ are as defined in claim
 33. 35. The compound ofclaim 34, wherein D is

wherein R³⁶ is independently hydrogen or C₁₋₆ alkyl; and R²⁰ ishydrogen.
 36. The compound of claim 33, wherein D is

wherein p is 0, 1, 2, 3 or 4; R³⁶ is independently hydrogen or R³⁰; andR²⁰ and R³⁰ are as defined in claim
 33. 37. The compound of claim 33,wherein D is

wherein X is CH₂, N, O or S; n is 1, 2, 3 or 4; p is 0, 1, 2,3 or 4; R³⁶is hydrogen or R³⁰; and R²⁰ and R³⁰ are as defined in claim
 33. 38. Thecompound of claim 33, wherein D is

wherein q is 0, 1, 2, 3, 4, 5 or 6; and R²⁰ and R³⁰ are as defined inclaim
 33. 39. The compound of claim 33, wherein D is

wherein Q is NR²⁰, O or S; X is CR^(38a)R^(38b), NR³⁶, O or S, X′ isCR^(39a)R^(39b), NR³⁶, O, S or SO₂, R³⁶, R^(37a), R^(37b), R^(38a) andR^(38b) are independently hydrogen or R³⁰; R^(39a) and R^(39b) areindependently hydrogen or R³⁰, or R^(39a) and R^(39b) are taken togetherwith the carbon atom to which they are attached to form a C₃₋₇cycloalkyl or C₃₋₇ heterocyclyl; and R²⁰ and R³⁰ are as defined in claim33.
 40. The compound of claim 39, wherein D is


41. The compound of claim 33, wherein D is

wherein q is 0, 1, 2, 3, 4, 5 or 6; G is independently C or N; G′ isindependently N, NR⁴⁶, CR^(47,) S or O; R⁴⁶ and R⁴⁷ are independentlyhydrogen or R⁴⁰; or two groups R⁴⁶ and R⁴⁷ are taken together to form aring; and R²⁰ and R⁴⁰ are as defined in claim
 33. 42. The compound ofclaim 41, wherein D is


43. The compound of claim 1, wherein R₁ is hydrogen, halo, or methyl.44. The compound of claim 43, wherein R₁ is fluoro.
 45. The compound ofclaim 1, wherein R₃ is hydrogen.
 46. The compound of claim 1, whereinthe compound is selected from the group consisting of Compound Nos. 1,2, 3, 4, 5, 6, 7, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 30, 31, 32, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 54, 55, 56, 57, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, 113, 115, 116, 117, 118, 119, 122, 123, 124, 125, 126, 127,128, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 143, 144, 145,146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 159, 160, 161,162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175,176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203,204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217,218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, and 230 inTable 1, or a pharmaceutically acceptable salt thereof.
 47. The compoundof claim 1, wherein the compound is selected from the group consistingof Compound Nos. 9-12, 29, 33-36, 53, 58, 64, 83, 84, 96, 97, 111, 112,114, 120, 121, 129, 137, 141, 142, 152 and 158 in Table 1 and CompoundNos, 231-390 in Table 2, or a pharmaceutically acceptable salt thereof.48. The compound of claim 1, wherein the compound is selected fromCompound Nos. 391-528 in Table 3, or a pharmaceutically acceptable saltthereof.
 49. A pharmaceutical composition comprising the compound ofclaim 1, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.
 50. The pharmaceutical compositionof claim 49, wherein said composition further comprises achemotherapeutic agent.
 51. A method of inhibiting HPK1 comprisingcontacting HPK1 in a subject with an effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 52. A method forenhancing an immune response in a subject in need thereof, comprisingadministering to the subject an effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 53. The methodof claim 52, wherein the subject has cancer.
 54. A method for treating aHPK1-dependent disorder comprising administering to a subject in needthereof an effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 55. The method of claim 54,wherein said HPK1-dependent disorder is a cancer.
 56. The method ofclaim 55, wherein the cancer comprises at least one cancer selected fromthe group consisting of colorectal cancer, melanoma, non-small cell lungcancer, ovarian cancer, breast cancer, pancreatic cancer, ahematological malignancy, and a renal cell carcinoma.
 57. The method ofclaim 56, further comprising administering a chemotherapeutic agent tothe subject.
 58. A method for making a compound of Formula I as definedin claim 1, wherein the method comprises the steps in Scheme 1 or Scheme2.